Shiau Celia E, Monk Kelly R, Joo William, Talbot William S
Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Cell Rep. 2013 Dec 12;5(5):1342-52. doi: 10.1016/j.celrep.2013.11.004. Epub 2013 Dec 5.
Microglia are phagocytic cells that form the basis of the brain's immune system. They derive from primitive macrophages that migrate into the brain during embryogenesis, but the genetic control of microglial development remains elusive. Starting with a genetic screen in zebrafish, we show that the noncanonical NOD-like receptor (NLR) nlrc3-like is essential for microglial formation. Although most NLRs trigger inflammatory signaling, nlrc3-like acts cell autonomously in microglia precursor cells to suppress unwarranted inflammation in the absence of overt immune challenge. In nlrc3-like mutants, primitive macrophages initiate a systemic inflammatory response with increased proinflammatory cytokines and actively aggregate instead of migrating into the brain to form microglia. NLRC3-like requires both its pyrin and NACHT domains, and it can bind the inflammasome component apoptosis-associated speck-like protein. Our studies suggest that NLRC3-like may regulate the inflammasome and other inflammatory pathways. Together, these results demonstrate that NLRC3-like prevents inappropriate macrophage activation, thereby allowing normal microglial development.
小胶质细胞是构成大脑免疫系统基础的吞噬细胞。它们起源于胚胎发育过程中迁移到大脑的原始巨噬细胞，但小胶质细胞发育的基因控制仍不清楚。从斑马鱼的基因筛选开始，我们发现非经典NOD样受体（NLR）nlrc3样对小胶质细胞的形成至关重要。尽管大多数NLR会触发炎症信号，但nlrc3样在小胶质细胞前体细胞中自主发挥作用，在没有明显免疫挑战的情况下抑制不必要的炎症。在nlrc3样突变体中，原始巨噬细胞会引发全身炎症反应，促炎细胞因子增加，并积极聚集，而不是迁移到大脑中形成小胶质细胞。NLRC3样需要其pyrin和NACHT结构域，并且它可以结合炎性小体成分凋亡相关斑点样蛋白。我们的研究表明，NLRC3样可能调节炎性小体和其他炎症途径。总之，这些结果表明NLRC3样可防止巨噬细胞的不适当激活，从而使小胶质细胞正常发育。
