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Thymic stromal lymphopoietin

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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.[1][2] It shares a common ancestor with IL-7.[3]

TSLP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTSLP, thymic stromal lymphopoietin
External IDsOMIM: 607003; MGI: 1855696; HomoloGene: 81957; GeneCards: TSLP; OMA:TSLP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

85480

53603

Ensembl

ENSG00000145777

ENSMUSG00000024379

UniProt

Q969D9

Q9JIE6

RefSeq (mRNA)

NM_033035
NM_138551

NM_021367

RefSeq (protein)

NP_149024
NP_612561

NP_067342

Location (UCSC)Chr 5: 111.07 – 111.08 MbChr 18: 32.95 – 32.95 Mb
PubMed search[6][7]
Wikidata
View/Edit HumanView/Edit Mouse

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.[1][2][8]

Gene ontology

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[1]) 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

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.[1]

TSLP

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

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

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.[1][13]

sfTSLP

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

A receptor for sfTSLP has not been discovered. It is not known whether sfTSLP also signals via the TSLP receptor complex.[15]

TSLP

Epithelium defense

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.[1]

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.[1][17]

Type 2 immune responses

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

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

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

Crystal structure of human TSLP in complex with TSLP-R and IL-7Ra (pdb 5j11)[22]

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.[1][23]

Disease

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

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

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

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

  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ a b c GRCh38: Ensembl release 89: ENSG00000145777 – Ensembl, May 2017
  5. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024379 – Ensembl, May 2017
  6. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  7. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  8. ^ 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.
  9. ^ 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.
  10. ^ a b "Entrez Gene: TSLP thymic stromal lymphopoietin".
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. (July 2002). "Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP" (PDF). Nature Immunology. 3 (7): 673–680. doi:10.1038/ni805. PMID 12055625. S2CID 9648786.
  29. ^ Demehri S, Morimoto M, Holtzman MJ, Kopan R (May 2009). "Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma". PLOS Biology. 7 (5): e1000067. doi:10.1371/journal.pbio.1000067. PMC 2700555. PMID 19557146.
  30. ^ "Tezspire- tezepelumab-ekko injection, solution". DailyMed. Retrieved 24 December 2021.
  31. ^ "Tezspire (tezepelumab) approved in the US for severe asthma". AstraZeneca (Press release). 17 December 2021. Retrieved 17 December 2021.
  32. ^ Park S, Park Y, Son SH, Lee K, Jung YW, Lee KY, et al. (October 2017). "Synthesis and biological evaluation of peptide-derived TSLP inhibitors". Bioorganic & Medicinal Chemistry Letters. 27 (20): 4710–4713. doi:10.1016/j.bmcl.2017.09.010. PMID 28927768.
  33. ^ Park BB, Choi JW, Park D, Choi D, Paek J, Kim HJ, et al. (June 2019). "Structure-Activity Relationships of Baicalein and its Analogs as Novel TSLP Inhibitors". Scientific Reports. 9 (1): 8762. Bibcode:2019NatSR...9.8762P. doi:10.1038/s41598-019-44853-5. PMC 6584507. PMID 31217492.
  34. ^ 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.
  • Overview of all the structural information available in the PDB for UniProt: Q969D9 (Thymic stromal lymphopoietin) at the PDBe-KB.
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