Glia maturation factor-gamma modulation of signaling pathways in macrophages

TLR4信号必须严格调控，以提供有效的免疫保护和避免炎症诱导的病理。因此，tlr4引发炎症反应的负性调控机制尤为重要。Glia mature factor-γ （GMFG）是一种在炎症细胞中表达的新型肌动蛋白解聚因子/cofilin超家族蛋白，与介导中性粒细胞和T细胞迁移有关，但其在巨噬细胞免疫应答中的功能尚不清楚。本研究在THP-1巨噬细胞和人原代巨噬细胞中研究了GMFG在lps诱导的tlr4信号通路中的作用。LPS刺激巨噬细胞降低GMFG mRNA和蛋白表达。我们发现，GMFG负调控lps诱导的NF- B-、MAPK-和irf3信号通路的激活，以及随后在人巨噬细胞中促炎细胞因子和I型IFN的产生。我们发现内源性GMFG定位于早期和晚期内体。GMFG敲低延迟了lps诱导的TLR4内化，并延长了TLR4在早期核内体的滞留时间，表明TLR4从早期核内体到晚期核内体的运输被中断，这可能有助于增强lps诱导的TLR4信号传导。综上所述，我们的研究结果表明，GMFG通过促进巨噬细胞中TLR4的内吞运输，作为TLR4信号的负调节因子。

TLR4 signaling must be tightly regulated to provide both effective immune protection and avoid inflammation-induced pathology. Thus, the mechanisms that negatively regulate the TLR4-triggered inflammatory response are of particular importance. Glia maturation factor-γ (GMFG), a novel actin depolymerization factor/cofilin superfamily protein that is expressed in inflammatory cells, has been implicated in mediating neutrophil and T cell migration, but its function in macrophage immune response remains unclear. In the current study, the role of GMFG in the LPS-induced TLR4-signaling pathway was investigated in THP-1 macrophages and human primary macrophages. LPS stimulation of macrophages decreased GMFG mRNA and protein expression. We show that GMFG negatively regulates LPS-induced activation of NF-κB-, MAPK-, and IRF3-signaling pathways and subsequent production of proinflammatory cytokines and type I IFN in human macrophages. We found that endogenous GMFG localized within early and late endosomes. GMFG knockdown delayed LPS-induced TLR4 internalization and caused prolonged TLR4 retention at the early endosome, suggesting that TLR4 transport from early to late endosomes is interrupted, which may contribute to enhanced LPS-induced TLR4 signaling. Taken together, our findings suggest that GMFG functions as a negative regulator of TLR4 signaling by facilitating TLR4 endocytic trafficking in macrophages.