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The TLR4-NOS1-AP1 signaling axis regulates macrophage polarization.

Author information

Affiliations

  • 1. Center for Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, 453552, MP, India.
      Authors
    • Srivastava M 1
    • Naim A 1
    • Roy A 1
    • Baig MS 1
    (4 authors)
  • 2. Discipline of Chemistry, School of Basic Sciences, Indian Institute of Technology Indore (IITI), Indore, MP, India.
      Authors
    • Saqib U 2
    (1 author)
  • 3. Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA.
      Authors
    • Liu D 3
    (1 author)
  • 4. School of Biochemistry, Devi Ahilya Vishwa Vidyalaya, Indore, MP, India.
      Authors
    • Bhatnagar D 4
    (1 author)
  • 5. Sophisticated Instrumentation Center (SIC), Indian Institute of Technology Indore (IITI), Indore, MP, India.
      Authors
    • Ravinder R 5
    (1 author)

ORCIDs linked to this article

Inflammation Research : Official Journal of the European Histamine Research Society ... [et al.], 24 Dec 2016, 66(4):323-334
https://doi.org/10.1007/s00011-016-1017-z PMID: 28013342 

Abstract 

Objective

Macrophages polarize to proinflammatory M1 or anti-inflammatory M2 states with distinct physiological functions. This transition within the M1-M2 phenotypes decides the nature, duration and severity of an inflammatory response. Although there is a substantial understanding of the fate of these phenotypes, the underlying molecular mechanism of transition within the M1-M2 phenotypes is not well understood. We have investigated the role of neuronal nitric oxide synthase (NOS1)-mediated regulation of activator protein 1 (AP-1) transcription factor in macrophages as a critical effector of macrophage phenotypic change.

Materials and methods

Raw 264.7 and THP1 macrophages were stimulated with LPS (250 ng/ml) to activate the inflammatory signaling pathway. We analyzed the effect of pharmacological NOS1 inhibitor: TRIM (1-(2- Trifluoromethylphenyl) imidazole) on LPS-induced inflammatory response in macrophages.

Results

We determined that NOS1-derived nitric oxide (NO) facilitate Fos and Jun interaction which induces IL-12 & IL-23 expression. Pharmacological inhibition of NOS1 inhibits ATF2 and Jun dimer. Switching of Fos and Jun dimer to ATF2 and Jun dimerization controls phenotype transition from IL-12high IL-23high IL-10low to IL-12low IL-23lowIL-10high phenotype, respectively.

Conclusion

These findings highlight a key role of the TLR4-NOS1-AP1 signaling axis in regulating macrophage polarization.

Full text links 

Read article at publisher's site: https://doi.org/10.1007/s00011-016-1017-z

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Funding 

Funders who supported this work.

Department of Biotechnology, Ministry of Science and Technology