TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis.

TIMAP (TGFβ-inhibited membrane-associated protein) is an endothelium-enriched TGFβ downstream protein and structurally belongs to the targeting subunit of myosin phosphatase; however, the mechanism of TGFβ repressing TIMAP and its functional relevance to TGFβ bioactivity remain largely unknown. Here, we report that TIMAP is reduced in TGFβ-elevated mouse fibrotic kidney and highly expressed in macrophages. TGFβ repression of TIMAP is associated with HDAC3 upregulation and its recruitment by Smad2/3 at the Smad binding element on TIMAP promoter, whereas specific HDAC3 inhibition reversed the TIMAP repression, suggesting that TGFβ transcriptionally downregulates TIMAP through HDAC3-associated Smad signaling. Further investigation showed that TIMAP over-expression interrupted TGFβ-associated Smad signaling and TIMAP repression by TGFβ correlated with TGFβ-induced macrophage M2 polarization markers, migration, and phagocytosis-the processes promoted by phosphorylation of the putative TIMAP substrate myosin light chain (MLC). Consistently, TIMAP dephosphorylated MLC in macrophages and TGFβ induced macrophage migration and phagocytosis in TIMAP- and MLC phosphorylation-dependent manners, suggesting that TIMAP dephosphorylation of MLC constitutes an essential regulatory loop mitigating TGFβ-associated macrophage M2 phenotypic activities. Given that hyperactive TGFβ often causes excessive macrophage phagocytic activities potentially leading to various chronic disorders, the strategies targeting HDAC3/TIMAP axis might improve TGFβ-associated pathological processes. TIMAP is enriched in the endothelium and highly expressed in macrophages. TIMAP is suppressed by TGFβ via HDAC3-associated Smad signaling. TIMAP inhibits TGFβ signaling and TGFβ-associated macrophage M2 polarization. TIMAP dephosphorylation of MLC counteracts TGFβ-induced macrophage phagocytosis.

Citation

Jun Yang, Shasha Yin, Fangfang Bi, Lin Liu, Tian Qin, Hongwei Wang, Wangsen Cao. TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis. Journal of molecular medicine (Berlin, Germany). 2017 Mar;95(3):273-285

PMID: 27709267

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