Abstract：
TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.
摘要：
TcpC是泌尿致病性大肠杆菌（UPEC）的多功能毒力因子。巨噬细胞可以分化为两个不同的亚群M1和M2，它们在抗感染免疫中起着不同的作用。这里,我们研究了TcpC对M1/M2极化的影响及其潜在机制。我们的数据显示M1标记CD86和iNOS被显著抑制,而M2标志物CD163、CD206和Arg-1在分泌TcpC的野生型CFT073（CFT073wt）感染的肾盂肾炎小鼠模型的肾脏巨噬细胞中增强，与TcpC敲除的CFT073突变体（CFT073Δtcpc）感染的小鼠肾脏中的巨噬细胞相比。CFT073wt或重组TcpC(rTcpC)处理抑制LPS+IFN-γ诱导的CD80、CD86、TNF-α和iNOS表达,但在人和小鼠巨噬细胞系THP-1和J774A.1中促进IL-4诱导的CD163，CD206，Arg-1和IL-10的表达。此外，rTcpC显著减弱LPS+IFN-γ诱导的p38，ERK，p50和p65但增强了IL-4诱导的Akt和STAT6的磷酸化。这些数据表明，TcpC抑制M1，但通过下调p38，ERK/NF-κB和上调Akt/STAT6信号通路促进M2巨噬细胞极化，分别。我们的发现不仅阐明了TcpC对巨噬细胞M1/M2极化及其相关信号通路的调节作用,而且还提供了TcpC介导的巨噬细胞介导的先天免疫的免疫逃避的新机制。
