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.
|Original language||English (US)|
|Number of pages||11|
|Journal||Journal of Innate Immunity|
|State||Published - Jan 1 2016|
Bibliographical noteFunding Information:
This work was supported by DK54733, DK60521, DK54733– 11S, DK60521–12S1 and the Dean’s Commitment and the Distinguished McKnight Professorship of University of Minnesota to L.-N.W. We thank Pei-Yao Liu and Raji Jasty for technical assistance.
- Endotoxin tolerance
- Macrophage polarization
- Receptor-interacting protein 140
- Wound healing