TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation
TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation
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DOI：
10.1073/pnas.2009778117
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发表时间：
2020-12-01
影响因子：
11.1
通讯作者：
Pasare, Chandrashekhar
中科院分区：
文献类型：
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作者：
Irizarry-Caro, Ricardo A.;McDaniel, Margaret M.;Pasare, Chandrashekhar
巨噬细胞对微生物配体和各种有害信号的反应是通过启动炎症反应来消除最初的致病性损伤。然而，巨噬细胞从促炎状态到修复状态的转变对于炎症的解决和恢复稳态至关重要。控制这一转变的分子参与者仍然定义不清。在这里，我们发现修复性巨噬细胞转变由PI3K的B细胞适配器（BCAP）决定。由于长期的肠道炎症和受损的组织修复，携带巨噬细胞特异性BCAP缺失的小鼠不能从葡聚糖硫酸钠诱导的结肠炎中恢复并死于结肠炎。在微生物刺激后，WT巨噬细胞中的基因表达从早期炎症特征转变为晚期修复特征，这一过程在BCAP缺陷型巨噬细胞中受到阻碍。我们发现BCAP的缺乏阻碍了FOXO 1和GSK 3 β的失活，这有助于它们增强炎症状态。BCAP缺乏还导致有氧糖酵解缺陷和乳酸产生减少。这转化为组蛋白乳酸化减少和修复性巨噬细胞基因表达减少。因此，我们的研究结果表明，BCAP是一个关键的细胞内在开关，通过印记表观遗传变化调节炎性巨噬细胞向修复性巨噬细胞的转变。
Macrophages respond to microbial ligands and various noxious cues by initiating an inflammatory response aimed at eliminating the original pathogenic insult. Transition of macrophages from a proinflammatory state to a reparative state, however, is vital for resolution of inflammation and return to homeostasis. The molecular players governing this transition remain poorly defined. Here, we find that the reparative macrophage transition is dictated by B-cell adapter for PI3K (BCAP). Mice harboring a macrophage-specific deletion of BCAP fail to recover from and succumb to dextran sulfate sodium-induced colitis due to prolonged intestinal inflammation and impaired tissue repair. Following microbial stimulation, gene expression in WT macrophages switches from an early inflammatory signature to a late reparative signature, a process that is hampered in BCAP-deficient macrophages. We find that absence of BCAP hinders inactivation of FOXO1 and GSK3 beta, which contributes to their enhanced inflammatory state. BCAP deficiency also results in defective aerobic glycolysis and reduced lactate production. This translates into reduced histone lactylation and decreased expression of reparative macrophage genes. Thus, our results reveal BCAP to be a critical cell-intrinsic switch that regulates transition of inflammatory macrophages to reparative macrophages by imprinting epigenetic changes.