Falahee Patrick C, Anderson Leif S, Reynolds Mack B, Pirir Mauricio, McLaughlin Bridget E, Dillen Carly A, Cheung Ambrose L, Miller Lloyd S, Simon Scott I
Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616.
Comprehensive Cancer Center Flow Cytometry Shared Resource, University of California, Davis, Davis, CA 95616.
J Immunol. 2017 Sep 1;199(5):1772-1782. doi: 10.4049/jimmunol.1700649. Epub 2017 Jul 21.
The immune response to infection in skin involves the recruitment of polymorphonuclear neutrophils (PMNs) from the bone marrow via the circulation and local granulopoiesis from hematopoietic stem and progenitor cells (HSPCs) that also traffic to infected skin wounds. We focus on regulation of PMN number and function and the role of pore-forming α-toxin (AT), a virulence factor that causes host cell lysis and elicits inflammasome-mediated IL-1β secretion in wounds. Infection with wild-type enriched in AT reduced PMN recruitment and resulted in sustained bacterial burden and delayed wound healing. In contrast, PMN recruitment to wounds infected with an isogenic AT-deficient strain was unimpeded, exhibiting efficient bacterial clearance and hastened wound resolution. HSPCs recruited to infected wounds were unaffected by AT production and were activated to expand PMN numbers in proportion to abundance in a manner regulated by TLR2 and IL-1R signaling. Immunodeficient MyD88-knockout mice infected with experienced lethal sepsis that was reversed by PMN expansion mediated by injection of wild-type HSPCs directly into wounds. We conclude that AT-induced IL-1β promotes local granulopoiesis and effective resolution of -infected wounds, revealing a potential antibiotic-free strategy for tuning the innate immune response to treat methicillin-resistant infection in immunodeficient patients.
皮肤对感染的免疫反应涉及多形核中性粒细胞（PMN）从骨髓经循环募集，以及造血干细胞和祖细胞（HSPC）在局部进行粒细胞生成，这些细胞也会迁移至感染的皮肤伤口处。我们着重研究PMN数量和功能的调节，以及成孔α毒素（AT）的作用，AT是一种毒力因子，可导致宿主细胞裂解，并在伤口处引发炎性小体介导的白细胞介素-1β分泌。感染富含AT的野生型菌株会减少PMN募集，导致细菌负荷持续存在并延迟伤口愈合。相比之下，PMN募集到感染了同基因AT缺陷菌株的伤口处不受阻碍，表现出有效的细菌清除和加速的伤口愈合。募集到感染伤口处的HSPC不受AT产生的影响，并被激活以按TLR2和IL-1R信号调节的方式，与菌株丰度成比例地扩增PMN数量。感染该菌株的免疫缺陷MyD88基因敲除小鼠会发生致命性败血症，通过直接向伤口注射野生型HSPC介导的PMN扩增可逆转这种情况。我们得出结论，AT诱导的白细胞介素-1β促进局部粒细胞生成和有效解决该菌株感染的伤口，揭示了一种潜在的无抗生素策略，用于调节先天性免疫反应以治疗免疫缺陷患者的耐甲氧西林该菌株感染。
