MafB is a critical regulator of complement component C1q

Mai Tran ,Hyojung Jeon,Motochika Hattori,Risa Kamei,Christina-Sylvia Andrea,Risako Shiraishi,Risa Fujii,Takashi Kudo,Kohei Asano ,Toshiaki Usui,Hisashi Oishi,Megumi Nakamura,Yuki Tsunakawa,Makoto Kobayashi,Yurina Matsunaga,Kaushalya Kulathunga,Yuki Imamura,Ryusuke Koshida,Michito Hamada,Satoru Takahashi

doi:10.1038/s41467-017-01711-0

Abstract

The transcription factor MafB is expressed by monocytes and macrophages. Efferocytosis (apoptotic cell uptake) by macrophages is important for inhibiting the development of autoimmune diseases, and is greatly reduced in Mafb-deficient macrophages. Here, we show the expression of the first protein in the classical complement pathway C1q is important for mediating efferocytosis and is reduced in Mafb-deficient macrophages. The efferocytosis defect in Mafb-deficient macrophages can be rescued by adding serum from wild-type mice, but not by adding serum from C1q-deficient mice. By hemolysis assay we also show that activation of the classical complement pathway is decreased in Mafb-deficient mice. In addition, MafB overexpression induces C1q-dependent gene expression and signals that induce C1q genes are less effective in the absence of MafB. We also show that Mafb-deficiency can increase glomerular autoimmunity, including anti-nuclear antibody deposition. These results show that MafB is an important regulator of C1q.

Highlights

The transcription factor MafB is expressed by monocytes and macrophages
The results showed that the numbers of Mafb−/− macrophages that engulfed or bound the fluorescent apoptotic cells were significantly reduced at 30, 60, and 120 min compared with WT macrophages (Fig. 1b, c)
C1q is the first protein in the classical complement pathway and is important for efferocytosis, which inhibits the development of autoimmune disease

Summary

Introduction

Efferocytosis (apoptotic cell uptake) by macrophages is important for inhibiting the development of autoimmune diseases, and is greatly reduced in Mafb-deficient macrophages. We show the expression of the first protein in the classical complement pathway C1q is important for mediating efferocytosis and is reduced in Mafb-deficient macrophages. We show that Mafbdeficiency can increase glomerular autoimmunity, including anti-nuclear antibody deposition These results show that MafB is an important regulator of C1q. C1q binds phosphatidylserine on early apoptotic cells via gC1q and prompts efferocytosis by macrophages. CD11b and CellTracker double-positive populations represent macrophages that bind and/or engulf apoptotic cells. C The percentage of binding or uptake of apoptotic cells was increased in a time-dependent manner in WT but not Mafb−/− (WT, n = 5; Mafb−/−, n = 6).

Methods

Results

Conclusion