CXCL9 Contributes to Antimicrobial Protection of the Gut during <i>Citrobacter rodentium</i> Infection Independent of Chemokine-Receptor Signaling

Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1-/- mice and CXCR3-/- mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.趋化因子（Chemokines）已被证实可在体外作为有效杀菌分子，对多种细菌与真菌发挥直接抗菌活性。此类直接抗菌效应与其介导免疫受体参与的趋化活性相互独立。然而，这类蛋白质在宿主防御过程中，尤其是对抗肠道病原体时可能发挥的直接生物学功能，目前仍知之甚少。本研究显示，ELR-趋化因子CXCL9可对鼠柠檬酸杆菌（Citrobacter rodentium）——一种感染肠道黏膜的黏附/抹去（attaching/effacing）病原体——展现直接抗菌活性。体内通过抗CXCL9抗体抑制该抗菌活性后，宿主对鼠柠檬酸杆菌感染的易感性显著升高，表现为细菌大量侵入肠隐窝、细菌载量增加以及组织病理损伤加重。借助Rag1基因敲除（Rag1-/-）小鼠与CXCR3基因敲除（CXCR3-/-）小鼠，本研究证实CXCL9在保护肠道黏膜中的作用不依赖于适应性免疫应答或其免疫受体CXCR3。最后，本研究提供证据表明，吞噬细胞与自然杀伤（NK）细胞协同发挥作用，以启动针对鼠柠檬酸杆菌的强效CXCL9应答。上述研究结果揭示了免疫细胞来源的CXCL9趋化因子在介导肠道黏膜保护性抗菌应答中的全新功能。