Richardson Edward T, Shukla Supriya, Sweet David R, Wearsch Pamela A, Tsichlis Philip N, Boom W Henry, Harding Clifford V
Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Medical Scientist Training Program, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
Infect Immun. 2015 Jun;83(6):2242-54. doi: 10.1128/IAI.00135-15. Epub 2015 Mar 16.
Mycobacterium tuberculosis survives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrict M. tuberculosis to latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-γ), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by which M. tuberculosis modulates host responses to promote its survival remain unclear. In these studies, we demonstrate that M. tuberculosis induction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion of Tpl2 blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate that M. tuberculosis regulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway in Tpl2(-/-) macrophages enhances Th1 polarization and IFN-γ production by antigen-specific CD4(+) T cells responding to M. tuberculosis infection. These data indicate that M. tuberculosis and its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.
结核分枝杆菌在巨噬细胞内存活，并采用免疫逃避机制在宿主体内持续存在。诱导产生保护性1型辅助性T细胞（Th1）反应，大多数个体的免疫反应足以将结核分枝杆菌限制为潜伏感染，但大多数感染并未完全消除。随着T细胞和巨噬细胞做出反应，在与保护性Th1相关的细胞因子和其他促炎细胞因子（如白细胞介素-12（IL-12）、干扰素γ（IFN-γ）和肿瘤坏死因子α）以及抗炎细胞因子（如IL-10）之间建立了平衡。结核分枝杆菌调节宿主反应以促进其存活的机制仍不清楚。在这些研究中，我们证明结核分枝杆菌诱导感染的巨噬细胞产生IL-10、抑制IL-12以及抑制II类主要组织相容性复合体（MHC-II）分子，均由Toll样受体2（TLR2）依赖性激活细胞外信号调节激酶（ERK）驱动。用U0126进行药理抑制或Tpl2基因缺失消除TLR2下游的ERK信号，可阻断IL-10分泌并增强IL-12 p70分泌。我们证明结核分枝杆菌对巨噬细胞中这些途径的调节会影响T细胞对感染巨噬细胞的反应。因此，Tpl2（-/-）巨噬细胞中ERK途径的基因阻断增强了抗原特异性CD4（+）T细胞对结核分枝杆菌感染的Th1极化和IFN-γ产生。这些数据表明，结核分枝杆菌及其强效TLR2配体激活巨噬细胞中的ERK信号，以促进抗炎性巨噬细胞反应并减弱针对病原体的Th1反应。
