Thymic stromal lymphopoietin: Difference between revisions
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{{Short description|Cytokine, alarmin, and growth factor.}} |
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{{Infobox_gene}} |
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| ⚫ | '''Thymic stromal lymphopoietin''' ('''TSLP''') is an [[Interleukin 2|interleukin (IL)-2]]-like [[cytokine]], [[alarmin]], and [[growth factor]] involved in numerous [[physiological]] and [[pathological]] processes, primarily those of the [[immune system]].<ref name="Ebina-Shibuya_2023">{{cite journal | vauthors = Ebina-Shibuya R, Leonard WJ | title = Role of thymic stromal lymphopoietin in allergy and beyond | journal = Nature Reviews. Immunology | volume = 23 | issue = 1 | pages = 24–37 | date = January 2023 | pmid = 35650271 | doi = 10.1038/s41577-022-00735-y | pmc = 9157039 }}</ref><ref name="Tsilingiri_2017">{{cite journal | vauthors = Tsilingiri K, Fornasa G, Rescigno M | title = Thymic Stromal Lymphopoietin: To Cut a Long Story Short | journal = Cellular and Molecular Gastroenterology and Hepatology | volume = 3 | issue = 2 | pages = 174–182 | date = March 2017 | pmid = 28275684 | doi = 10.1016/j.jcmgh.2017.01.005 | pmc = 5331833 }}</ref> It [[Paralog|shares a common ancestor]] with [[Interleukin 7|IL-7]].<ref name="Piliponsky_2016">{{cite journal | vauthors = Piliponsky AM, Lahiri A, Truong P, Clauson M, Shubin NJ, Han H, Ziegler SF | title = Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 55 | issue = 2 | pages = 264–274 | date = August 2016 | pmid = 26934097 | pmc = 4979369 | doi = 10.1165/rcmb.2015-0380OC }}</ref> |
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Originally appreciated for its role in [[immune cell]] [[Cell proliferation|proliferation]] and development, and then for its pivotal role in [[Type 2 inflammation|type 2 immune responses]], TSLP is now |
Originally appreciated for its role in [[immune cell]] [[Cell proliferation|proliferation]] and development, and then for its pivotal role in [[Type 2 inflammation|type 2 immune responses]], TSLP is now known to be involved in other types of [[Immune response|immune responses]], [[autoimmune disease]], and certain [[Cancer|cancers]].<ref name="Ebina-Shibuya_2023" /><ref name="Tsilingiri_2017" /><ref>{{cite journal | vauthors = Corren J, Ziegler SF | title = TSLP: from allergy to cancer | journal = Nature Immunology | volume = 20 | issue = 12 | pages = 1603–1609 | date = December 2019 | pmid = 31745338 | doi = 10.1038/s41590-019-0524-9 | s2cid = 208171881 }}</ref> |
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== Gene ontology == |
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TSLP production has been observed in numerous species, including [[Human|humans]] and [[mice]]. |
TSLP production has been observed in numerous species, including [[Human|humans]] and [[mice]]. |
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In humans, TSLP is encoded by the ''TSLP'' [[gene]].<ref name="pmid11480573">{{cite journal | vauthors = Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD | title = Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation | journal = Leukemia | volume = 15 | issue = 8 | pages = 1286–1292 | date = August 2001 | pmid = 11480573 | doi = 10.1038/sj.leu.2402175 | s2cid = 12658276 | doi-access = }}</ref><ref name="entrez" /> [[Alternative splicing]] of ''TSLP'' results in two [[transcript variants]], a long form (lfTSLP, or just TSLP<ref name="Ebina-Shibuya_2023" />) consisting of 159 [[amino acid residues]], and a short form (sfTSLP) consisting of 63 amino acid residues.<ref name="entrez">{{cite web | title = Entrez Gene: TSLP thymic stromal lymphopoietin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85480}}</ref><ref name="Harada_2009">{{cite journal | vauthors = Harada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K, Miyatake A, Enomoto T, Noguchi E, Yoshihara S, Ebisawa M, Saito H, Matsumoto K, Nakamura Y, Ziegler SF, Tamari M | display-authors = 6 | title = Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 40 | issue = 3 | pages = 368–374 | date = March 2009 | pmid = 18787178 | doi = 10.1165/rcmb.2008-0041OC }}</ref> |
In humans, TSLP is encoded by the ''TSLP'' [[gene]].<ref name="pmid11480573">{{cite journal | vauthors = Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD | title = Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation | journal = Leukemia | volume = 15 | issue = 8 | pages = 1286–1292 | date = August 2001 | pmid = 11480573 | doi = 10.1038/sj.leu.2402175 | s2cid = 12658276 | doi-access = }}</ref><ref name="entrez" /> [[Alternative splicing]] of ''TSLP'' results in two [[transcript variants]], a long form (lfTSLP, or just TSLP<ref name="Ebina-Shibuya_2023" />) consisting of 159 [[amino acid residues]], and a short form (sfTSLP) consisting of 63 amino acid residues. These variants use different initiation [[methionine]] [[codons]] and share a [[carboxy terminus]].<ref name="entrez">{{cite web | title = Entrez Gene: TSLP thymic stromal lymphopoietin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85480}}</ref><ref name="Harada_2009">{{cite journal | vauthors = Harada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K, Miyatake A, Enomoto T, Noguchi E, Yoshihara S, Ebisawa M, Saito H, Matsumoto K, Nakamura Y, Ziegler SF, Tamari M | display-authors = 6 | title = Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 40 | issue = 3 | pages = 368–374 | date = March 2009 | pmid = 18787178 | doi = 10.1165/rcmb.2008-0041OC }}</ref> |
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=== sfTSLP === |
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sfTSLP [[Messenger RNA|mRNA]] is [[constitutively expressed]] in normal human [[Respiratory epithelium#Cells|bronchial epithelial cells]] (NHBE), normal human lung fibroblasts (NHLF), and [[Bronchus#Structure|bronchial smooth muscle cells]] (BSMC).<ref name="Harada_2009" /> sfTSLP mRNA expression is not significantly upregulated by [[inflammation]].<ref name="Ebina-Shibuya_2023" /> |
sfTSLP [[Messenger RNA|mRNA]] is [[constitutively expressed]] in normal human [[Respiratory epithelium#Cells|bronchial epithelial cells]] (NHBE), normal human lung fibroblasts (NHLF), and [[Bronchus#Structure|bronchial smooth muscle cells]] (BSMC).<ref name="Harada_2009" /> sfTSLP mRNA expression is not significantly upregulated by [[inflammation]].<ref name="Ebina-Shibuya_2023" /> |
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=== TSLP === |
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TSLP mRNA is not constitutively expressed in NHBE and has a low level of constitutive expression in NHLF and BSMC. TSLP mRNA expression is upregulated by certain [[Toll-like receptor#Ligands|Toll-like receptor (TLR) ligands]] such as [[flagellin]] and [[poly(I:C)]], but not by [[Lipopolysaccharide|lipopolysaccharide (LPS)]] or [[Macrophage-activating lipopeptide 2|macrophage-activating lipopeptide 2 (MALP-2)]].<ref name="Harada_2009" /> |
TSLP mRNA is not constitutively expressed in NHBE and has a low level of constitutive expression in NHLF and BSMC. TSLP mRNA expression is upregulated by certain [[Toll-like receptor#Ligands|Toll-like receptor (TLR) ligands]] such as [[flagellin]] and [[poly(I:C)]], but not by [[Lipopolysaccharide|lipopolysaccharide (LPS)]] or [[Macrophage-activating lipopeptide 2|macrophage-activating lipopeptide 2 (MALP-2)]].<ref name="Harada_2009" /> |
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== Discovery == |
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As the name suggests, TSLP was initially discovered as a growth factor derived from the [[supernatant]] of a [[mouse]] [[Thymus|thymic]] [[Stromal cell|stromal]] [[cell line]] that was found to promote the [[Cell survival|survival]] and proliferation of [[B lymphocytes]].<ref>{{cite journal | vauthors = Friend SL, Hosier S, Nelson A, Foxworthe D, Williams DE, Farr A | title = A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells | journal = Experimental Hematology | volume = 22 | issue = 3 | pages = 321–328 | date = March 1994 | pmid = 8112430 | url = https://pubmed.ncbi.nlm.nih.gov/8112430/ }}</ref> |
As the name suggests, TSLP was initially discovered as a growth factor derived from the [[supernatant]] of a [[mouse]] [[Thymus|thymic]] [[Stromal cell|stromal]] [[cell line]] that was found to promote the [[Cell survival|survival]] and proliferation of [[B lymphocytes]].<ref>{{cite journal | vauthors = Friend SL, Hosier S, Nelson A, Foxworthe D, Williams DE, Farr A | title = A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells | journal = Experimental Hematology | volume = 22 | issue = 3 | pages = 321–328 | date = March 1994 | pmid = 8112430 | url = https://pubmed.ncbi.nlm.nih.gov/8112430/ }}</ref> |
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== Function == |
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TSLP was initially observed to have both [[pro-inflammatory]] and [[anti-inflammatory]] activity. It is now clear that this seemingly ambivalent action can actually be divided between the two [[transcript variants]], with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory.<ref name="Ebina-Shibuya_2023" /><ref name=" |
TSLP was initially observed to have both [[pro-inflammatory]] and [[anti-inflammatory]] activity. It is now clear that this seemingly ambivalent action can actually be divided between the two [[transcript variants]], with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory.<ref name="Ebina-Shibuya_2023" /><ref name="Fornasa_2015">{{cite journal | vauthors = Fornasa G, Tsilingiri K, Caprioli F, Botti F, Mapelli M, Meller S, Kislat A, Homey B, Di Sabatino A, Sonzogni A, Viale G, Diaferia G, Gori A, Longhi R, Penna G, Rescigno M | display-authors = 6 | title = Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin | journal = The Journal of Allergy and Clinical Immunology | volume = 136 | issue = 2 | pages = 413–422 | date = August 2015 | pmid = 26014813 | doi = 10.1016/j.jaci.2015.04.011 | pmc = 4534776 }}</ref> |
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=== sfTSLP === |
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sfTSLP |
sfTSLP [[inhalation]] prevents [[Respiratory epithelium|airway epithelial barrier]] disruption caused by the inhalation of [[House dust mite|house dust mite (HDM)]] [[Antigen|antigens]] in mice who had been sensitised to HDM, an [[asthma]]-like model.<ref>{{cite journal |display-authors=6 |vauthors=Dong H, Hu Y, Liu L, Zou M, Huang C, Luo L, Yu C, Wan X, Zhao H, Chen J, Xie Z, Le Y, Zou F, Cai S |date=December 2016 |title=Distinct roles of short and long thymic stromal lymphopoietin isoforms in house dust mite-induced asthmatic airway epithelial barrier disruption |journal=Scientific Reports |volume=6 |issue=1 |pages=39559 |bibcode=2016NatSR...639559D |doi=10.1038/srep39559 |pmc=5171874 |pmid=27996052}}</ref> Similarly, sfTSLP reduces the severity of [[Dextran sulphate sodium|dextran sulphate sodium (DSS)]]-induced [[colitis]] in mice, a model of [[Inflammatory bowel disease|inflammatory bowel disease (IBD)]], and prevents [[endotoxic shock]] and [[sepsis]] resulting from [[bacterial infections]].<ref name="Fornasa_2015" /> |
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==== Signalling ==== |
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A receptor for sfTSLP has not been discovered. It is not known whether sfTSLP also signals via the [[#Signalling 2|TSLP receptor complex]].<ref name="Smolinska_2023">{{cite journal | vauthors = Smolinska S, Antolín-Amérigo D, Popescu FD, Jutel M | title = Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma | journal = International Journal of Molecular Sciences | volume = 24 | issue = 16 | pages = 12725 | date = August 2023 | pmid = 37628907 | doi = 10.3390/ijms241612725 | pmc = 10454039 | doi-access = free }}</ref> |
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=== TSLP === |
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==== Epithelium defense ==== |
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TSLP's pivotal role in initiating immune responses begins with its release by [[Epithelial cell|epithelial]] or [[Stromal cell|stromal cells]] of the [[Lung|lungs]], [[skin]], or [[gastrointestinal tract]] as an [[alarmin]] following [[Cell injury|mechanical cell injury]], [[Pattern recognition receptor|pattern recognition receptor (PRR)]] and [[Protease-activated receptor|protease-activated receptor (PAR)]] activation, stimulation by certain cytokines, chemical irritation, or infection.<ref name="Ebina-Shibuya_2023" /> |
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| ⚫ | When local [[Mast cell|mast cells]] bind an [[allergen]], they produce TSLP indirectly by releasing [[tryptase]] in an [[FcεRI]]-dependent manner, activating PARs on epithelial cells and causing them to release TSLP.<ref>{{cite journal | vauthors = Redhu D, Franke K, Aparicio-Soto M, Kumari V, Pazur K, Illerhaus A, Hartmann K, Worm M, Babina M | display-authors = 6 | title = Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase/protease-activated receptor 2 axis | journal = The Journal of Allergy and Clinical Immunology | volume = 149 | issue = 6 | pages = 2053–2061.e6 | date = June 2022 | pmid = 35240143 | doi = 10.1016/j.jaci.2022.01.029 | doi-access = free }}</ref> Unlike [[IL-33]], a similarly acting alarmin, TSLP is usually not constitutively expressed and must be [[upregulated]] by [[Transcription factor|transcription factors]] such as [[NF-κB|nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)]] or [[Activator protein 1|activator protein (AP)1]] following insult.<ref name="Ebina-Shibuya_2023" /><ref>{{cite journal | vauthors = Saluja R, Zoltowska A, Ketelaar ME, Nilsson G | title = IL-33 and Thymic Stromal Lymphopoietin in mast cell functions | journal = European Journal of Pharmacology | volume = 778 | pages = 68–76 | date = May 2016 | pmid = 26051792 | doi = 10.1016/j.ejphar.2015.04.047 | series = Pharmacological modulation of Mast cells and Basophils }}</ref> |
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===== Type 2 immune responses ===== |
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Local [[Dendritic cell|dendritic cells (DCs)]] are among the most important targets of TSPL, as they, among other [[Antigen-presenting cell|antigen presenting cells (APCs)]], allow the immune system to mount [[Adaptive immune response|adaptive responses]]. TSLP signalling grants DCs the exact phenotype needed to prime [[T helper cell#Activation of naive helper T cells|naive CD<sub>4</sub><sup>+</sup> T cells]] into [[T helper cell#Th1/Th2 model|T<sub>H</sub>2]] pro-inflammatory cells, or producing [[Type 2 cytokine|type 2 cytokines]], namely by [[Upregulation|upregulating]] [[OX40L]], [[CD80]], and [[CD86]]. TSLP-stimulated DCs that migrate into draining lymph nodes can prime CD<sub>4</sub><sup>+</sup> T cells into [[Follicular B helper T cells|follicular helper T (T<sub>FH</sub>) cells]], which in turn can promote [[Immunoglobulin G|immunoglobulin (Ig)G]] and [[Immunoglobulin E|E]] production by resident B lymphocytes, thus initiating type 2 immune responses. T<sub>H</sub>2 can also facilitate [[Class switch|B cell class switching]] towards IgE.<ref>{{Cite journal |last1=Poulsen |first1=Lars K. |last2=Hummelshoj |first2=Lone |date=July 2009 |title=Triggers of IgE class switching and allergy development |url=http://www.tandfonline.com/doi/full/10.1080/07853890701449354 |journal=Annals of Medicine |language=en |volume=39 |issue=6 |pages=440–456 |doi=10.1080/07853890701449354 |pmid=17852040 |s2cid=37162812 |issn=0785-3890}}</ref> |
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===== Type 1 and 3 immune responses ===== |
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As mentioned, TSLP serves as an alarmin following TLR binding by certain [[Pathogen-associated molecular pattern|pathogen-associated molecular patterns (PAMPs)]], including viral and bacterial ones, rather than just irritation by allergens. Thus, TSLP also plays an early role in the initiation of type 1 and 3 immune responses to pathogens. This activity has thus far been best described in the respiratory mucosa.<ref name=":0">{{cite journal |vauthors=Cao L, Qian W, Li W, Ma Z, Xie S |date=2023-09-22 |title=Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response |journal=Frontiers in Immunology |volume=14 |pages=1250541 |doi=10.3389/fimmu.2023.1250541 |pmc=10556530 |pmid=37809098 |doi-access=free}}</ref> |
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TSLP-activated CD<sub>11</sub>b<sup>+</sup> DCs can promote the proliferation and long-term survival of CD<sub>8</sub><sup>+</sup> cytotoxic T cells, promoting the development of lasting adaptive cellular immunity. Analogously, TSLP-activated CD<sub>11</sub>c<sup>+</sup> cells are essential for the development of IgA antibodies following pneumococcal infection. TSLP also holds considerable promise as a novel vaccine adjuvant and anti-cancer immunotherapy due to its broad and potent alarmin functionality, as is evidenced by numerous animal studies.<ref name=":0" /> |
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==== Germinal centre formation ==== |
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[[Germinal center|Germinal centres (GCs)]] are microstructures that form in [[secondary lymphoid organs]] during immune responses. GCs are the sites of the [[Clone (B-cell)|clonal expansion of B lymphocytes]] and the [[Affinity maturation|affinity maturation of their antibodies]], thus allowing the immune system to generate antibodies with a high affinity for antigens.<ref>{{Cite journal |last1=Victora |first1=Gabriel D. |last2=Nussenzweig |first2=Michel C. |date=2022-04-26 |title=Germinal Centers |url=https://www.annualreviews.org/doi/10.1146/annurev-immunol-120419-022408 |journal=Annual Review of Immunology |language=en |volume=40 |issue=1 |pages=413–442 |doi=10.1146/annurev-immunol-120419-022408 |pmid=35113731 |issn=0732-0582|doi-access=free }}</ref> TSLP may play an important role in the formation of GCs, as the depletion of TSPLR in CD<sub>4</sub><sup>+</sup> T cells prevented their formation in mice, as well as the generation of [[IgG1]].<ref>{{Cite journal |last1=Domeier |first1=Phillip P. |last2=Rahman |first2=Ziaur S.M. |last3=Ziegler |first3=Steven F. |date=2023-01-06 |title=B- and T-cell-intrinsic regulation of germinal centers by thymic stromal lymphopoietin signaling |journal=Science Immunology |volume=8 |issue=79 |pages=eadd9413 |doi=10.1126/sciimmunol.add9413 |issn=2470-9468 |pmid=36608149|pmc=10162646 }}</ref> |
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[[File:TSLP wiki 5j11.png|left|thumb|350x350px|Crystal structure of human TSLP in complex with TSLP-R and IL-7Ra (pdb 5j11)<ref name="Verstraete_2017" />]] |
[[File:TSLP wiki 5j11.png|left|thumb|350x350px|Crystal structure of human TSLP in complex with TSLP-R and IL-7Ra (pdb 5j11)<ref name="Verstraete_2017" />]] |
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TSLP signals through a heterodimeric receptor complex composed of |
TSLP signals through a [[heterodimeric]] [[receptor complex]] composed of [[CRLF2|the TSLP receptor (TSLPR)]] and the [[Interleukin-7 receptor-α|IL-7Rα]] chain. Upon binding, [[Janus kinase 1|Janus kinase (JAK)1]] and [[Janus kinase 2|2]] are activated, leading to the activation of [[STAT5A|signal transducer and activator of transcription (STAT)5A]] and [[STAT5B|5B]] and, to a lesser extent, [[STAT1]] and [[STAT3|3]]. These [[Transcription factor|transcription factors]] upregulate pro-inflammatory cytokines such as [[Interleukin 4|IL-4]], [[Interleukin 5|5]], [[Interleukin 9|9]], and [[Interleukin 13|13]].<ref name="Ebina-Shibuya_2023" /><ref name="pmid10570284">{{cite journal |vauthors=Isaksen DE, Baumann H, Trobridge PA, Farr AG, Levin SD, Ziegler SF |date=December 1999 |title=Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction |journal=Journal of Immunology |volume=163 |issue=11 |pages=5971–5977 |doi=10.4049/jimmunol.163.11.5971 |pmid=10570284 |s2cid=7211559 |doi-access=free}}</ref> |
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== Disease == |
== Disease == |
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TSLP expression is linked to many disease states including asthma,<ref name="pmid15944327">{{cite journal | vauthors = Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C | display-authors = 6 | title = Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity | journal = Journal of Immunology | volume = 174 | issue = 12 | pages = 8183–8190 | date = June 2005 | pmid = 15944327 | doi = 10.4049/jimmunol.174.12.8183 | doi-access = free }}</ref> inflammatory arthritis,<ref name="pmid17416344">{{cite journal | vauthors = Koyama K, Ozawa T, Hatsushika K, Ando T, Takano S, Wako M, Suenaga F, Ohnuma Y, Ohba T, Katoh R, Sugiyama H, Hamada Y, Ogawa H, Okumura K, Nakao A | display-authors = 6 | title = A possible role for TSLP in inflammatory arthritis | journal = Biochemical and Biophysical Research Communications | volume = 357 | issue = 1 | pages = 99–104 | date = May 2007 | pmid = 17416344 | doi = 10.1016/j.bbrc.2007.03.081 }}</ref> atopic dermatitis,<ref name="pmid17320941">{{cite journal | vauthors = Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N | title = Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells | journal = The Journal of Allergy and Clinical Immunology | volume = 119 | issue = 4 | pages = 982–990 | date = April 2007 | pmid = 17320941 | doi = 10.1016/j.jaci.2007.01.003 }}</ref> eczema, eosinophilic esophagitis and other allergic states.<ref name="pmid14999427">{{cite journal | vauthors = Soumelis V, Liu YJ | title = Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation | journal = Springer Seminars in Immunopathology | volume = 25 | issue = 3–4 | pages = 325–333 | date = February 2004 | pmid = 14999427 | doi = 10.1007/s00281-003-0152-0 | s2cid = 9713181 }}</ref><ref name="pmid12055625">{{cite journal | vauthors = Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt Rd R, Bazan F, Kastelein RA, Liu YJ | display-authors = 6 | title = Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP | journal = Nature Immunology | volume = 3 | issue = 7 | pages = 673–680 | date = July 2002 | pmid = 12055625 | doi = 10.1038/ni805 | s2cid = 9648786 | url = https://eprints.ucm.es/id/eprint/9340/1/17.Soumelis_Reche_etal_NI_2002.pdf }}</ref> The factors inducing the activation of TSLP release are not clearly defined. |
TSLP expression is linked to many disease states including asthma,<ref name="pmid15944327">{{cite journal | vauthors = Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C | display-authors = 6 | title = Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity | journal = Journal of Immunology | volume = 174 | issue = 12 | pages = 8183–8190 | date = June 2005 | pmid = 15944327 | doi = 10.4049/jimmunol.174.12.8183 | doi-access = free }}</ref> inflammatory arthritis,<ref name="pmid17416344">{{cite journal | vauthors = Koyama K, Ozawa T, Hatsushika K, Ando T, Takano S, Wako M, Suenaga F, Ohnuma Y, Ohba T, Katoh R, Sugiyama H, Hamada Y, Ogawa H, Okumura K, Nakao A | display-authors = 6 | title = A possible role for TSLP in inflammatory arthritis | journal = Biochemical and Biophysical Research Communications | volume = 357 | issue = 1 | pages = 99–104 | date = May 2007 | pmid = 17416344 | doi = 10.1016/j.bbrc.2007.03.081 }}</ref> atopic dermatitis,<ref name="pmid17320941">{{cite journal | vauthors = Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N | title = Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells | journal = The Journal of Allergy and Clinical Immunology | volume = 119 | issue = 4 | pages = 982–990 | date = April 2007 | pmid = 17320941 | doi = 10.1016/j.jaci.2007.01.003 }}</ref> eczema, eosinophilic esophagitis and other allergic states.<ref name="pmid14999427">{{cite journal | vauthors = Soumelis V, Liu YJ | title = Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation | journal = Springer Seminars in Immunopathology | volume = 25 | issue = 3–4 | pages = 325–333 | date = February 2004 | pmid = 14999427 | doi = 10.1007/s00281-003-0152-0 | s2cid = 9713181 }}</ref><ref name="pmid12055625">{{cite journal | vauthors = Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt Rd R, Bazan F, Kastelein RA, Liu YJ | display-authors = 6 | title = Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP | journal = Nature Immunology | volume = 3 | issue = 7 | pages = 673–680 | date = July 2002 | pmid = 12055625 | doi = 10.1038/ni805 | s2cid = 9648786 | url = https://eprints.ucm.es/id/eprint/9340/1/17.Soumelis_Reche_etal_NI_2002.pdf }}</ref> The factors inducing the activation of TSLP release are not clearly defined. |
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=== Asthma === |
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TSLP has thus far primarily been described as playing a role in type 2 inflammatory diseases, such as type 2-high asthma and atopic dermatitis. However, TSLP's many functions are increasingly being implicating in other disease states, including autoimmune diseases and cancers. |
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Expression of TSLP is enhanced under [[asthma]]-like conditions (aka [[bronchial hyperresponsiveness|Airway HyperResponsiveness]] or AHR model in the mouse), conditioning [[antigen-presenting cells|APCs]] in order to orient the differentiation of T cells coming into the lungs towards a [[T helper cell|TH2]] profile (T helper 2 pathway).{{Citation needed|date=September 2008}} The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways.{{Citation needed|date=January 2011}} |
Expression of TSLP is enhanced under [[asthma]]-like conditions (aka [[bronchial hyperresponsiveness|Airway HyperResponsiveness]] or AHR model in the mouse), conditioning [[antigen-presenting cells|APCs]] in order to orient the differentiation of T cells coming into the lungs towards a [[T helper cell|TH2]] profile (T helper 2 pathway).{{Citation needed|date=September 2008}} The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways.{{Citation needed|date=January 2011}} |
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=== Atopic dermatitis === |
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TSLP-activated Langerhans cells of the [[epidermis (skin)|epidermis]] induce the production of [[pro-inflammatory cytokine]]s like [[TNF-alpha]] by T cells potentially causing [[atopic dermatitis]].<ref name="pmid17320941"/> It is thought that by understanding the mechanism of TSLP production and those potential substances that block the production, one may be able to prevent or treat conditions of asthma and/or eczema.<ref name="pmid19557146">{{cite journal | vauthors = Demehri S, Morimoto M, Holtzman MJ, Kopan R | title = Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma | journal = PLOS Biology | volume = 7 | issue = 5 | pages = e1000067 | date = May 2009 | pmid = 19557146 | pmc = 2700555 | doi = 10.1371/journal.pbio.1000067 | doi-access = free }} |
TSLP-activated Langerhans cells of the [[epidermis (skin)|epidermis]] induce the production of [[pro-inflammatory cytokine]]s like [[TNF-alpha]] by T cells potentially causing [[atopic dermatitis]].<ref name="pmid17320941"/> It is thought that by understanding the mechanism of TSLP production and those potential substances that block the production, one may be able to prevent or treat conditions of asthma and/or eczema.<ref name="pmid19557146">{{cite journal | vauthors = Demehri S, Morimoto M, Holtzman MJ, Kopan R | title = Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma | journal = PLOS Biology | volume = 7 | issue = 5 | pages = e1000067 | date = May 2009 | pmid = 19557146 | pmc = 2700555 | doi = 10.1371/journal.pbio.1000067 | doi-access = free }} |
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*{{lay source |template=cite news |date=24 May 2009 |title=Eczema's link to asthma uncovered |url=http://news.bbc.co.uk/2/hi/health/8055038.stm |work=BBC News}}</ref> |
*{{lay source |template=cite news |date=24 May 2009 |title=Eczema's link to asthma uncovered |url=http://news.bbc.co.uk/2/hi/health/8055038.stm |work=BBC News}}</ref> |
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| ⚫ | |||
==== Cancer ==== |
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Type 2 inflammation has been shown to promote tumorigenesis and metastasis. However, TSLP's role in cancer goes far beyond its initiation and perpetuation of type 2 inflammation, as is suggested by the fact that many cancers harbor TSLP mutations. |
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===== Type 2 inflammation-dependent cancer promotion ===== |
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One of the roles of type 2 inflammation is preventing excessive type 1 inflammation by deactivating type 1 inflammatory cells or switching them towards a type 2-promoting phenotype. |
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| ⚫ | |||
The TSLP signaling axis is an attractive therapeutic target. Amgen's [[Tezepelumab]], a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma.<ref name="Tezspire FDA label">{{cite web | title=Tezspire- tezepelumab-ekko injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=60f0aa03-ad25-4d48-80ce-7fcfa76f325f | access-date=24 December 2021}}</ref><ref name="AstraZeneca PR 20211217">{{cite press release | title=Tezspire (tezepelumab) approved in the US for severe asthma | website=AstraZeneca | date=17 December 2021 | url=https://www.astrazeneca.com/media-centre/press-releases/2021/tezspire-tezepelumab-approved-in-the-us-for-severe-asthma.html | access-date=17 December 2021}}</ref> Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed.<ref name="Verstraete_2017">{{pdb|5J11}}; {{cite journal | vauthors = Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, Vandenberghe I, Pauwels K, Tavernier J, Lambrecht BN, Hammad H, De Winter H, Beyaert R, Lippens G, Savvides SN | display-authors = 6 | title = Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma | journal = Nature Communications | volume = 8 | pages = 14937 | date = April 2017 | pmid = 28368013 | pmc = 5382266 | doi = 10.1038/ncomms14937 | bibcode = 2017NatCo...814937V }} </ref> Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface,<ref name="pmid28927768">{{cite journal | vauthors = Park S, Park Y, Son SH, Lee K, Jung YW, Lee KY, Jeon YH, Byun Y | display-authors = 6 | title = Synthesis and biological evaluation of peptide-derived TSLP inhibitors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 27 | issue = 20 | pages = 4710–4713 | date = October 2017 | pmid = 28927768 | doi = 10.1016/j.bmcl.2017.09.010 }} </ref> natural products <ref name="pmid31217492">{{cite journal | vauthors = Park BB, Choi JW, Park D, Choi D, Paek J, Kim HJ, Son SY, Mushtaq AU, Shin H, Kim SH, Zhou Y, Lim T, Park JY, Baek JY, Kim K, Kwon H, Son SH, Chung KY, Jeong HJ, Kim HM, Jung YW, Lee K, Lee KY, Byun Y, Jeon YH | display-authors = 6 | title = Structure-Activity Relationships of Baicalein and its Analogs as Novel TSLP Inhibitors | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 8762 | date = June 2019 | pmid = 31217492 | pmc = 6584507 | doi = 10.1038/s41598-019-44853-5 | bibcode = 2019NatSR...9.8762P }} </ref> and computational fragment-based screening.<ref name="pmid29222519">{{cite journal | vauthors = Van Rompaey D, Verstraete K, Peelman F, Savvides SN, Augustyns K, Van Der Veken P, De Winter H | title = Virtual screening for inhibitors of the human TSLP:TSLPR interaction | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 17211 | date = December 2017 | pmid = 29222519 | pmc = 5722893 | doi = 10.1038/s41598-017-17620-7 | bibcode = 2017NatSR...717211V }} </ref> |
The TSLP signaling axis is an attractive therapeutic target. Amgen's [[Tezepelumab]], a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma.<ref name="Tezspire FDA label">{{cite web | title=Tezspire- tezepelumab-ekko injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=60f0aa03-ad25-4d48-80ce-7fcfa76f325f | access-date=24 December 2021}}</ref><ref name="AstraZeneca PR 20211217">{{cite press release | title=Tezspire (tezepelumab) approved in the US for severe asthma | website=AstraZeneca | date=17 December 2021 | url=https://www.astrazeneca.com/media-centre/press-releases/2021/tezspire-tezepelumab-approved-in-the-us-for-severe-asthma.html | access-date=17 December 2021}}</ref> Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed.<ref name="Verstraete_2017">{{pdb|5J11}}; {{cite journal | vauthors = Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, Vandenberghe I, Pauwels K, Tavernier J, Lambrecht BN, Hammad H, De Winter H, Beyaert R, Lippens G, Savvides SN | display-authors = 6 | title = Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma | journal = Nature Communications | volume = 8 | pages = 14937 | date = April 2017 | pmid = 28368013 | pmc = 5382266 | doi = 10.1038/ncomms14937 | bibcode = 2017NatCo...814937V }} </ref> Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface,<ref name="pmid28927768">{{cite journal | vauthors = Park S, Park Y, Son SH, Lee K, Jung YW, Lee KY, Jeon YH, Byun Y | display-authors = 6 | title = Synthesis and biological evaluation of peptide-derived TSLP inhibitors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 27 | issue = 20 | pages = 4710–4713 | date = October 2017 | pmid = 28927768 | doi = 10.1016/j.bmcl.2017.09.010 }} </ref> natural products <ref name="pmid31217492">{{cite journal | vauthors = Park BB, Choi JW, Park D, Choi D, Paek J, Kim HJ, Son SY, Mushtaq AU, Shin H, Kim SH, Zhou Y, Lim T, Park JY, Baek JY, Kim K, Kwon H, Son SH, Chung KY, Jeong HJ, Kim HM, Jung YW, Lee K, Lee KY, Byun Y, Jeon YH | display-authors = 6 | title = Structure-Activity Relationships of Baicalein and its Analogs as Novel TSLP Inhibitors | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 8762 | date = June 2019 | pmid = 31217492 | pmc = 6584507 | doi = 10.1038/s41598-019-44853-5 | bibcode = 2019NatSR...9.8762P }} </ref> and computational fragment-based screening.<ref name="pmid29222519">{{cite journal | vauthors = Van Rompaey D, Verstraete K, Peelman F, Savvides SN, Augustyns K, Van Der Veken P, De Winter H | title = Virtual screening for inhibitors of the human TSLP:TSLPR interaction | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 17211 | date = December 2017 | pmid = 29222519 | pmc = 5722893 | doi = 10.1038/s41598-017-17620-7 | bibcode = 2017NatSR...717211V }} </ref> |
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== References == |
== References == |
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{{reflist | 2}} |
{{reflist | 2}} |
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== Further reading == |
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{{refbegin | 2}} |
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* {{cite journal | vauthors = Ziegler SF, Liu YJ | title = Thymic stromal lymphopoietin in normal and pathogenic T cell development and function | journal = Nature Immunology | volume = 7 | issue = 7 | pages = 709–714 | date = July 2006 | pmid = 16785889 | doi = 10.1038/ni1360 | s2cid = 26635282 }} |
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* {{cite journal | vauthors = Liu YJ | title = Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation | journal = The Journal of Allergy and Clinical Immunology | volume = 120 | issue = 2 | pages = 238–44; quiz 245-6 | date = August 2007 | pmid = 17666213 | doi = 10.1016/j.jaci.2007.06.004 | doi-access = free }} |
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* {{cite journal | vauthors = Gilliet M, Soumelis V, Watanabe N, Hanabuchi S, Antonenko S, de Waal-Malefyt R, Liu YJ | title = Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells | journal = The Journal of Experimental Medicine | volume = 197 | issue = 8 | pages = 1059–1063 | date = April 2003 | pmid = 12707303 | pmc = 2193883 | doi = 10.1084/jem.20030240 }} |
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* {{cite journal | vauthors = Watanabe N, Hanabuchi S, Marloie-Provost MA, Antonenko S, Liu YJ, Soumelis V | title = Human TSLP promotes CD40 ligand-induced IL-12 production by myeloid dendritic cells but maintains their Th2 priming potential | journal = Blood | volume = 105 | issue = 12 | pages = 4749–4751 | date = June 2005 | pmid = 15741223 | doi = 10.1182/blood-2004-09-3622 | doi-access = free }} |
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* {{cite journal | vauthors = Lee HC, Ziegler SF | title = Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFkappaB | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 3 | pages = 914–919 | date = January 2007 | pmid = 17213320 | pmc = 1783414 | doi = 10.1073/pnas.0607305104 | doi-access = free | bibcode = 2007PNAS..104..914L }} |
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* {{cite journal | vauthors = Zhang K, Shan L, Rahman MS, Unruh H, Halayko AJ, Gounni AS | title = Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 293 | issue = 2 | pages = L375–L382 | date = August 2007 | pmid = 17513456 | doi = 10.1152/ajplung.00045.2007 | s2cid = 32287026 }} |
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* {{cite journal | vauthors = Rochman I, Watanabe N, Arima K, Liu YJ, Leonard WJ | title = Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells | journal = Journal of Immunology | volume = 178 | issue = 11 | pages = 6720–6724 | date = June 2007 | pmid = 17513717 | doi = 10.4049/jimmunol.178.11.6720 | doi-access = free }} |
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* {{cite journal | vauthors = Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, Hippe A, Corrigan CJ, Dong C, Homey B, Yao Z, Ying S, Huston DP, Liu YJ | display-authors = 6 | title = IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells | journal = The Journal of Experimental Medicine | volume = 204 | issue = 8 | pages = 1837–1847 | date = August 2007 | pmid = 17635955 | pmc = 2118667 | doi = 10.1084/jem.20070406 }} |
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{{refend}} |
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== External links == |
== External links == |
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Latest revision as of 21:50, 4 February 2024
Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system.[5][6] It shares a common ancestor with IL-7.[7]
Originally appreciated for its role in immune cell proliferation and development, and then for its pivotal role in type 2 immune responses, TSLP is now known to be involved in other types of immune responses, autoimmune disease, and certain cancers.[5][6][8]
Gene ontology
[edit]TSLP production has been observed in numerous species, including humans and mice.
In humans, TSLP is encoded by the TSLP gene.[9][10] Alternative splicing of TSLP results in two transcript variants, a long form (lfTSLP, or just TSLP[5]) consisting of 159 amino acid residues, and a short form (sfTSLP) consisting of 63 amino acid residues. These variants use different initiation methionine codons and share a carboxy terminus.[10][11]
sfTSLP
[edit]sfTSLP mRNA is constitutively expressed in normal human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and bronchial smooth muscle cells (BSMC).[11] sfTSLP mRNA expression is not significantly upregulated by inflammation.[5]
TSLP
[edit]TSLP mRNA is not constitutively expressed in NHBE and has a low level of constitutive expression in NHLF and BSMC. TSLP mRNA expression is upregulated by certain Toll-like receptor (TLR) ligands such as flagellin and poly(I:C), but not by lipopolysaccharide (LPS) or macrophage-activating lipopeptide 2 (MALP-2).[11]
Discovery
[edit]As the name suggests, TSLP was initially discovered as a growth factor derived from the supernatant of a mouse thymic stromal cell line that was found to promote the survival and proliferation of B lymphocytes.[12]
Function
[edit]TSLP was initially observed to have both pro-inflammatory and anti-inflammatory activity. It is now clear that this seemingly ambivalent action can actually be divided between the two transcript variants, with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory.[5][13]
sfTSLP
[edit]sfTSLP inhalation prevents airway epithelial barrier disruption caused by the inhalation of house dust mite (HDM) antigens in mice who had been sensitised to HDM, an asthma-like model.[14] Similarly, sfTSLP reduces the severity of dextran sulphate sodium (DSS)-induced colitis in mice, a model of inflammatory bowel disease (IBD), and prevents endotoxic shock and sepsis resulting from bacterial infections.[13]
Signalling
[edit]A receptor for sfTSLP has not been discovered. It is not known whether sfTSLP also signals via the TSLP receptor complex.[15]
TSLP
[edit]Epithelium defense
[edit]TSLP's pivotal role in initiating immune responses begins with its release by epithelial or stromal cells of the lungs, skin, or gastrointestinal tract as an alarmin following mechanical cell injury, pattern recognition receptor (PRR) and protease-activated receptor (PAR) activation, stimulation by certain cytokines, chemical irritation, or infection.[5]
When local mast cells bind an allergen, they produce TSLP indirectly by releasing tryptase in an FcεRI-dependent manner, activating PARs on epithelial cells and causing them to release TSLP.[16] Unlike IL-33, a similarly acting alarmin, TSLP is usually not constitutively expressed and must be upregulated by transcription factors such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or activator protein (AP)1 following insult.[5][17]
Type 2 immune responses
[edit]Local dendritic cells (DCs) are among the most important targets of TSPL, as they, among other antigen presenting cells (APCs), allow the immune system to mount adaptive responses. TSLP signalling grants DCs the exact phenotype needed to prime naive CD4+ T cells into TH2 pro-inflammatory cells, or producing type 2 cytokines, namely by upregulating OX40L, CD80, and CD86. TSLP-stimulated DCs that migrate into draining lymph nodes can prime CD4+ T cells into follicular helper T (TFH) cells, which in turn can promote immunoglobulin (Ig)G and E production by resident B lymphocytes, thus initiating type 2 immune responses. TH2 can also facilitate B cell class switching towards IgE.[18]
Type 1 and 3 immune responses
[edit]As mentioned, TSLP serves as an alarmin following TLR binding by certain pathogen-associated molecular patterns (PAMPs), including viral and bacterial ones, rather than just irritation by allergens. Thus, TSLP also plays an early role in the initiation of type 1 and 3 immune responses to pathogens. This activity has thus far been best described in the respiratory mucosa.[19]
TSLP-activated CD11b+ DCs can promote the proliferation and long-term survival of CD8+ cytotoxic T cells, promoting the development of lasting adaptive cellular immunity. Analogously, TSLP-activated CD11c+ cells are essential for the development of IgA antibodies following pneumococcal infection. TSLP also holds considerable promise as a novel vaccine adjuvant and anti-cancer immunotherapy due to its broad and potent alarmin functionality, as is evidenced by numerous animal studies.[19]
Germinal centre formation
[edit]Germinal centres (GCs) are microstructures that form in secondary lymphoid organs during immune responses. GCs are the sites of the clonal expansion of B lymphocytes and the affinity maturation of their antibodies, thus allowing the immune system to generate antibodies with a high affinity for antigens.[20] TSLP may play an important role in the formation of GCs, as the depletion of TSPLR in CD4+ T cells prevented their formation in mice, as well as the generation of IgG1.[21]
Signalling
[edit]
TSLP signals through a heterodimeric receptor complex composed of the TSLP receptor (TSLPR) and the IL-7Rα chain. Upon binding, Janus kinase (JAK)1 and 2 are activated, leading to the activation of signal transducer and activator of transcription (STAT)5A and 5B and, to a lesser extent, STAT1 and 3. These transcription factors upregulate pro-inflammatory cytokines such as IL-4, 5, 9, and 13.[5][23]
Disease
[edit]TSLP expression is linked to many disease states including asthma,[24] inflammatory arthritis,[25] atopic dermatitis,[26] eczema, eosinophilic esophagitis and other allergic states.[27][28] The factors inducing the activation of TSLP release are not clearly defined.
Asthma
[edit]Expression of TSLP is enhanced under asthma-like conditions (aka Airway HyperResponsiveness or AHR model in the mouse), conditioning APCs in order to orient the differentiation of T cells coming into the lungs towards a TH2 profile (T helper 2 pathway).[citation needed] The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways.[citation needed]
Atopic dermatitis
[edit]TSLP-activated Langerhans cells of the epidermis induce the production of pro-inflammatory cytokines like TNF-alpha by T cells potentially causing atopic dermatitis.[26] It is thought that by understanding the mechanism of TSLP production and those potential substances that block the production, one may be able to prevent or treat conditions of asthma and/or eczema.[29]
Therapeutic targeting
[edit]The TSLP signaling axis is an attractive therapeutic target. Amgen's Tezepelumab, a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma.[30][31] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed.[22] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface,[32] natural products [33] and computational fragment-based screening.[34]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000145777 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024379 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d e f g h Ebina-Shibuya R, Leonard WJ (January 2023). "Role of thymic stromal lymphopoietin in allergy and beyond". Nature Reviews. Immunology. 23 (1): 24–37. doi:10.1038/s41577-022-00735-y. PMC 9157039. PMID 35650271.
- ^ a b Tsilingiri K, Fornasa G, Rescigno M (March 2017). "Thymic Stromal Lymphopoietin: To Cut a Long Story Short". Cellular and Molecular Gastroenterology and Hepatology. 3 (2): 174–182. doi:10.1016/j.jcmgh.2017.01.005. PMC 5331833. PMID 28275684.
- ^ Piliponsky AM, Lahiri A, Truong P, Clauson M, Shubin NJ, Han H, Ziegler SF (August 2016). "Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis". American Journal of Respiratory Cell and Molecular Biology. 55 (2): 264–274. doi:10.1165/rcmb.2015-0380OC. PMC 4979369. PMID 26934097.
- ^ Corren J, Ziegler SF (December 2019). "TSLP: from allergy to cancer". Nature Immunology. 20 (12): 1603–1609. doi:10.1038/s41590-019-0524-9. PMID 31745338. S2CID 208171881.
- ^ Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD (August 2001). "Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation". Leukemia. 15 (8): 1286–1292. doi:10.1038/sj.leu.2402175. PMID 11480573. S2CID 12658276.
- ^ a b "Entrez Gene: TSLP thymic stromal lymphopoietin".
- ^ a b c Harada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K, et al. (March 2009). "Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells". American Journal of Respiratory Cell and Molecular Biology. 40 (3): 368–374. doi:10.1165/rcmb.2008-0041OC. PMID 18787178.
- ^ Friend SL, Hosier S, Nelson A, Foxworthe D, Williams DE, Farr A (March 1994). "A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells". Experimental Hematology. 22 (3): 321–328. PMID 8112430.
- ^ a b Fornasa G, Tsilingiri K, Caprioli F, Botti F, Mapelli M, Meller S, et al. (August 2015). "Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin". The Journal of Allergy and Clinical Immunology. 136 (2): 413–422. doi:10.1016/j.jaci.2015.04.011. PMC 4534776. PMID 26014813.
- ^ Dong H, Hu Y, Liu L, Zou M, Huang C, Luo L, et al. (December 2016). "Distinct roles of short and long thymic stromal lymphopoietin isoforms in house dust mite-induced asthmatic airway epithelial barrier disruption". Scientific Reports. 6 (1): 39559. Bibcode:2016NatSR...639559D. doi:10.1038/srep39559. PMC 5171874. PMID 27996052.
- ^ Smolinska S, Antolín-Amérigo D, Popescu FD, Jutel M (August 2023). "Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma". International Journal of Molecular Sciences. 24 (16): 12725. doi:10.3390/ijms241612725. PMC 10454039. PMID 37628907.
- ^ Redhu D, Franke K, Aparicio-Soto M, Kumari V, Pazur K, Illerhaus A, et al. (June 2022). "Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase/protease-activated receptor 2 axis". The Journal of Allergy and Clinical Immunology. 149 (6): 2053–2061.e6. doi:10.1016/j.jaci.2022.01.029. PMID 35240143.
- ^ Saluja R, Zoltowska A, Ketelaar ME, Nilsson G (May 2016). "IL-33 and Thymic Stromal Lymphopoietin in mast cell functions". European Journal of Pharmacology. Pharmacological modulation of Mast cells and Basophils. 778: 68–76. doi:10.1016/j.ejphar.2015.04.047. PMID 26051792.
- ^ Poulsen, Lars K.; Hummelshoj, Lone (July 2009). "Triggers of IgE class switching and allergy development". Annals of Medicine. 39 (6): 440–456. doi:10.1080/07853890701449354. ISSN 0785-3890. PMID 17852040. S2CID 37162812.
- ^ a b Cao L, Qian W, Li W, Ma Z, Xie S (2023-09-22). "Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response". Frontiers in Immunology. 14: 1250541. doi:10.3389/fimmu.2023.1250541. PMC 10556530. PMID 37809098.
- ^ Victora, Gabriel D.; Nussenzweig, Michel C. (2022-04-26). "Germinal Centers". Annual Review of Immunology. 40 (1): 413–442. doi:10.1146/annurev-immunol-120419-022408. ISSN 0732-0582. PMID 35113731.
- ^ Domeier, Phillip P.; Rahman, Ziaur S.M.; Ziegler, Steven F. (2023-01-06). "B- and T-cell-intrinsic regulation of germinal centers by thymic stromal lymphopoietin signaling". Science Immunology. 8 (79): eadd9413. doi:10.1126/sciimmunol.add9413. ISSN 2470-9468. PMC 10162646. PMID 36608149.
- ^ a b PDB: 5J11; Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, et al. (April 2017). "Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma". Nature Communications. 8: 14937. Bibcode:2017NatCo...814937V. doi:10.1038/ncomms14937. PMC 5382266. PMID 28368013.
- ^ Isaksen DE, Baumann H, Trobridge PA, Farr AG, Levin SD, Ziegler SF (December 1999). "Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction". Journal of Immunology. 163 (11): 5971–5977. doi:10.4049/jimmunol.163.11.5971. PMID 10570284. S2CID 7211559.
- ^ Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. (June 2005). "Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity". Journal of Immunology. 174 (12): 8183–8190. doi:10.4049/jimmunol.174.12.8183. PMID 15944327.
- ^ Koyama K, Ozawa T, Hatsushika K, Ando T, Takano S, Wako M, et al. (May 2007). "A possible role for TSLP in inflammatory arthritis". Biochemical and Biophysical Research Communications. 357 (1): 99–104. doi:10.1016/j.bbrc.2007.03.081. PMID 17416344.
- ^ a b Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N (April 2007). "Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells". The Journal of Allergy and Clinical Immunology. 119 (4): 982–990. doi:10.1016/j.jaci.2007.01.003. PMID 17320941.
- ^ Soumelis V, Liu YJ (February 2004). "Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation". Springer Seminars in Immunopathology. 25 (3–4): 325–333. doi:10.1007/s00281-003-0152-0. PMID 14999427. S2CID 9713181.
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- Lay summary in: "Eczema's link to asthma uncovered". BBC News. 24 May 2009.
- ^ "Tezspire- tezepelumab-ekko injection, solution". DailyMed. Retrieved 24 December 2021.
- ^ "Tezspire (tezepelumab) approved in the US for severe asthma". AstraZeneca (Press release). 17 December 2021. Retrieved 17 December 2021.
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- ^ Van Rompaey D, Verstraete K, Peelman F, Savvides SN, Augustyns K, Van Der Veken P, De Winter H (December 2017). "Virtual screening for inhibitors of the human TSLP:TSLPR interaction". Scientific Reports. 7 (1): 17211. Bibcode:2017NatSR...717211V. doi:10.1038/s41598-017-17620-7. PMC 5722893. PMID 29222519.
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