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24.12.2016 | Original Research Paper

The TLR4–NOS1–AP1 signaling axis regulates macrophage polarization

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

Erschienen in: Inflammation Research | Ausgabe 4/2017

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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-12^high IL-23^high IL-10^low to IL-12^low IL-23^lowIL-10^high phenotype, respectively.

Conclusion

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

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Titel: The TLR4–NOS1–AP1 signaling axis regulates macrophage polarization
verfasst von: Mansi Srivastava
Uzma Saqib
Adnan Naim
Anjali Roy
Dongfang Liu
Deepak Bhatnagar
Ravinder Ravinder
Mirza Saqib Baig
Publikationsdatum: 24.12.2016
Verlag: Springer International Publishing
Erschienen in: Inflammation Research / Ausgabe 4/2017
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-016-1017-z

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The TLR4–NOS1–AP1 signaling axis regulates macrophage polarization