title: The TLR4-NOS1-AP1 signaling axis regulates macrophage polarization.
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.
  
  
  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-12highIL-23highIL-10lowto IL-12lowIL-23lowIL-10highphenotype, respectively.
  
  
  CONCLUSIONS
  These findings highlight a key role of the TLR4-NOS1-AP1 signaling axis in regulating macrophage polarization.
authors.affiliation: Center for Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, 453552, MP, India.
authors.forename: Mansi
authors.initials: M
authors.lastname: Srivastava
authors.affiliation: Discipline of Chemistry, School of Basic Sciences, Indian Institute of Technology Indore (IITI), Indore, MP, India.
authors.forename: Uzma
authors.initials: U
authors.lastname: Saqib
authors.affiliation: Center for Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, 453552, MP, India.
authors.forename: Adnan
authors.initials: A
authors.lastname: Naim
authors.affiliation: Center for Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, 453552, MP, India.
authors.forename: Anjali
authors.initials: A
authors.lastname: Roy
authors.affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of Biochemistry, Devi Ahilya Vishwa Vidyalaya, Indore, MP, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhatnagar
authors.affiliation: Sophisticated Instrumentation Center (SIC), Indian Institute of Technology Indore (IITI), Indore, MP, India.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Ravinder
authors.affiliation: Center for Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, 453552, MP, India. msb@iiti.ac.in.
authors.forename: Mirza Saqib
authors.initials: MS
authors.lastname: Baig
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D016207:Cytokines; D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: Activator protein 1 (AP-1); Inflammation; Lipopolysaccharide (LPS); Macrophage; Neuronal nitric oxide synthase (NOS1); Proinflammatory cytokines