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.
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.
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.
© 2015 S. Karger AG, Basel.
- Endotoxin tolerance
- Macrophage polarization
- Receptor-interacting protein 140
- Wound healing