Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation.
Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation.
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DOI：
10.1242/dmm.047589
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发表时间：
2021-03-18
影响因子：
4.3
通讯作者：
Lech M
中科院分区：
文献类型：
--
作者：
Dobosz E;Lorenz G;Ribeiro A;Würf V;Wadowska M;Kotlinowski J;Schmaderer C;Potempa J;Fu M;Koziel J;Lech M
骨髓来源的细胞，特别是巨噬细胞，越来越多地被认为是免疫和耐受平衡的关键调节剂。然而，它们是否引发自身免疫性疾病或使疾病进展在副现象方面永久化仍不确定。在这里，我们表明，在巨噬细胞和粒细胞（Mcpip 1fl/fl-LysMcre+ C57 BL/6小鼠）中MCPIP 1的耗尽足以引发严重的自身免疫性疾病。这一点通过B细胞和浆细胞的扩增以及自身抗体（包括抗dsDNA、抗Smith和抗组蛋白抗体）的自发产生得到证明。因此，我们在6个月大的小鼠中记录了严重皮肤炎症、肺炎和肾小球IgG沉积以及系膜增生性肾炎的组织病理学证据。这些现象与全身性自身炎症有关，其继发地诱导一组细胞因子如Baff、IL 5、IL 9和Cd 40 L，影响适应性免疫应答。因此，异常的巨噬细胞活化是参与免疫耐受丧失的关键因素。总体而言，我们证明了MCPIP 1仅在骨髓细胞中的缺乏触发系统性狼疮样自身免疫，并且骨髓细胞活化的控制是系统性自身免疫发展中的关键检查点。总结：对骨髓MCPIP 1缺陷的小鼠的分析揭示了骨髓MCPIP 1在从自身炎症向自身免疫的转变中的功能以及巨噬细胞依赖性免疫激活作为继发性自身免疫的触发剂的作用。
Myeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined. Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance. Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity. Summary: Analyses of mice deficient in myeloid MCPIP1 reveal a function of myeloid MCPIP1 in the transition from autoinflammation to autoimmunity and a role for macrophage-dependent immune activation as a trigger of secondary autoimmunity.
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影响因子：
7.3
作者：
Malkiel S;Barlev AN;Atisha-Fregoso Y;Suurmond J;Diamond B
通讯作者：
Diamond B
影响因子：
4.4
作者：
Higuchi, T;Aiba, Y;Tsubata, T
通讯作者：
Tsubata, T
影响因子：
2.6
作者：
Harigai, M;Hara, M;Kashiwazaki, S
通讯作者：
Kashiwazaki, S
DOI：
10.1084/jem.20092641
发表时间：
2010-12-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liang J;Saad Y;Lei T;Wang J;Qi D;Yang Q;Kolattukudy PE;Fu M
通讯作者：
Fu M
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I