title: Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization.
abstract: Macrophage classical (M1) versus alternative (M2) polarization is critical for the homeostatic control of innate immunity. Uncontrolled macrophage polarization is frequently implicated in diseases. This study reports a new functional role for receptor-interacting protein 140 (RIP140) in regulating this phenotypic switch. RIP140 is required for M1 activation, and its degradation is critical to LPS-induced endotoxin tolerance (ET). Here, we found that failure to establish RIP140 degradation-mediated ET prevents M2 polarization, and reducing RIP140 level facilitates an M1/M2 switch, resulting in more efficient wound healing in animal models generated with either transgenic or bone marrow transplant procedures. The M2-suppressive effect is elicited by a new function of RIP140 that, in macrophages exposed to M2 cues, is exported to cytosol, forming complexes with CAPNS1 (calpain regulatory subunit) to activate calpain 1/2, that activates PTP1B phosphatase. The activated PTP1B then reduces STAT6 phosphorylation, thereby suppressing the efficiency of M2 polarization. It is concluded that RIP140 plays dual roles in regulating the M1-M2 phenotype switch: the first, in the nucleus, is an M1 enhancer and the second, in the cytosol, is an M2 suppressor. Modulating the level and/or subcellular distribution of RIP140 can be a new therapeutic strategy for diseases where inflammatory/anti-inflammatory responses are critical.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minn., USA.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Lin
authors.forename: Bomi
authors.initials: B
authors.lastname: Lee
authors.forename: Pu-Ste
authors.initials: PS
authors.lastname: Liu
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D016764:Cell Polarity; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004731:Endotoxins / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism; D000078723:Nuclear Receptor Interacting Protein 1; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000276:immunology / Q000378:metabolism*; D059748:Proteolysis; D050800:STAT6 Transcription Factor / Q000737:chemistry* / Q000276:immunology; D015398:Signal Transduction; D014945:Wound Healing
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004731:Endotoxins; D008070:Lipopolysaccharides; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D002154:Calpain; C484806:CAPN1 protein, human; C527669:CAPNS1 protein, human; C569870:CAPN2 protein, human