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Bcl6 modulates innate immunity by controlling macrophage activity and plays critical role in experimental autoimmune encephalomyelitis

Li, Q;Zhou, L;Wang, L;Li, S;Xu, G;Gu, H;Li, D;Liu, M;Fang, L;Wang, Z;Han, S;Zheng, B;

The B-cell CLL/lymphoma 6 (Bcl6) oncogenic repressor is a master regulator of humoral immunity and B-cell lymphomagenesis. Whereas much research has focused on its regulation and function of germinal center B cells and T cells, the role of Bcl6 in regulating the functions of innate immunity is not well defined. Here, we demonstrated that experimental autoimmune encephalomyelitis (EAE) is exacerbated in LysM Cre+/- Bcl6fl/fl mice. Although other cells such as neutrophils might be involved in this conditional mutant mouse model, we found that the disease pathology is mainly associated with a biased M1 macrophage activity and an enhanced encephalitogenic CD4+ Th17 cell response. In addition, LPS-induced sepsis mice exhibited an enhanced M1 and inhibited M2 response, further confirming that Bcl6 has an important role in regulating macrophage polarization. Mechanistically, Bcl6 interacts with IB and interferes its binding to the Il-6 (interleukin-6) promotor in macrophages, leading to a suppressed transcription of Il-6. These findings have demonstrated that Bcl6 exerts its regulatory function mainly by repressing Il-6 expression in macrophages. Thus, our study presents a novel role for Bcl6 in regulating immune response and inflammation. Interaction between Bcl6 and IB in macrophages may provide a potential therapeutic target for autoimmune inflammatory disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.