Control of <i>Listeria monocytogenes</i> infection requires classical IL-6 signaling in myeloid cells

IL-6 is required for the response of mice against Listeria monocytogenes. Control of infection depends on classical IL-6 signaling via membrane IL-6Rα, but IL-6 target cells and protective mechanisms remain unclear. We used mice with IL-6Rα-deficiency in T cells (Il6rafl/fl×CD4cre) or myeloid cells (Il6rafl/fl×LysMcre) to define the role of these cells in IL-6-mediated protection. Abrogation of IL-6Rα in T cells did not interfere with bacteria control and induction of TH1 and CD8+ T-cell responses. IL-6Rα-deficiency in myeloid cells caused significant defects in listeria control. This defect was not associated with reduced recruitment of granulocytes and inflammatory monocytes, and both cell populations were activated and not impaired in cytokine production. However, IL-6Rα-deficient inflammatory monocytes displayed diminished expression of IL-4Rα and of CD38, a protein required for phagocytosis and innate control of listeria. In vitro studies revealed that IL-4 and IL-6 cooperated in induction of CD38. In listeria-infected mice, phagocytic activity of inflammatory monocytes correlated with CD38 expression levels on cells and inflammatory monocytes of Il6rafl/fl×LysMcre mice were significantly impaired in phagocytosis. In conclusion, we demonstrate that inhibition of classical IL-6 signaling in myeloid cells causes alterations in differentiation and function of these cells, which subsequently prevent effective control of L. monocytogenes.白介素6（IL-6）是小鼠对抗单核细胞增生李斯特菌（Listeria monocytogenes）免疫应答所必需的。感染的控制依赖于经由膜结合型IL-6受体α（membrane IL-6Rα）介导的经典IL-6信号通路，但IL-6的靶细胞及其保护性免疫机制目前仍不明确。本研究使用T细胞中IL-6Rα缺陷的小鼠（Il6rafl/fl×CD4cre）或髓系细胞中IL-6Rα缺陷的小鼠（Il6rafl/fl×LysMcre），以明确这些细胞在IL-6介导的免疫保护中的作用。T细胞中IL-6Rα的敲除并不会影响细菌清除以及TH1型和CD8+ T细胞应答的诱导。髓系细胞中的IL-6Rα缺陷则会导致单核细胞增生李斯特菌清除出现显著缺陷。该缺陷与粒细胞和炎性单核细胞的招募减少无关，且这两类细胞均处于活化状态，细胞因子的产生功能未受损伤。然而，IL-6Rα缺陷的炎性单核细胞中，IL-4受体α（IL-4Rα）与CD38的表达均出现下调；CD38是吞噬作用以及单核细胞增生李斯特菌固有清除所必需的蛋白。体外实验证实，IL-4与IL-6可协同诱导CD38的表达。在单核细胞增生李斯特菌感染的小鼠中，炎性单核细胞的吞噬活性与细胞表面CD38的表达水平呈正相关，且Il6rafl/fl×LysMcre小鼠的炎性单核细胞吞噬功能出现显著损伤。综上，本研究证实，髓系细胞中经典IL-6信号通路的抑制会导致这些细胞的分化与功能异常，进而无法有效清除单核细胞增生李斯特菌（L. monocytogenes）。