The TLR4–NOS1–AP1 signaling axis regulates macrophage polarization

Mansi Srivastava, Uzma Saqib, Adnan Naim, Anjali Roy, Dongfang Liu, Deepak Bhatnagar, Ravinder Ravinder, Mirza Saqib Baig

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)323-334
Number of pages12
JournalInflammation Research
Issue number4
StatePublished - Apr 1 2017


  • Activator protein 1 (AP-1)
  • Inflammation
  • Lipopolysaccharide (LPS)
  • Macrophage
  • Neuronal nitric oxide synthase (NOS1)
  • Proinflammatory cytokines

ASJC Scopus subject areas

  • Immunology
  • Pharmacology


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