Journal
JOURNAL OF INNATE IMMUNITY
Volume 8, Issue 1, Pages 97-107Publisher
KARGER
DOI: 10.1159/000433539
Keywords
Receptor-interacting protein 140; Macrophage polarization; Endotoxin tolerance; Wound healing; Inflammation; PTP1B; STAT6
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Funding
- University of Minnesota [DK54733, DK60521, DK54733-11S, DK60521-12S1]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK054733, R01DK060521] Funding Source: NIH RePORTER
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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. (C) 2015 S. Karger AG, Basel
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