Olfactomedin 4 down-regulates neutrophil killing of Gram-positive and Gram-negat

慢性肉芽肿病（CGD）患者有复发威胁生命的细菌和真菌感染。Olfactomedin 4 （OLFM4）是一种负性调节宿主对细菌感染防御的中性粒细胞颗粒蛋白。本研究的目的是在小鼠x连锁CGD模型中评估Olfm4缺失对宿主防御金黄色葡萄球菌和烟曲霉的影响。在这里，我们假设CGD中性粒细胞中Olfm4的缺失可能通过非氧化机制恢复微生物杀灭活性。

Chronic granulomatous disease (CGD) patients have recurrent life-threatening bacterial and fungal infections. Olfactomedin 4 (OLFM4) is a neutrophil granule protein that negatively regulates host defense against bacterial infection. The goal of this study was to evaluate the impact of Olfm4 deletion on host defense against Staphylococcus aureus and Aspergillus fumigatus in a murine X-linked CGD model. Here we hypothesize that deletion of Olfm4 in CGD neutrophils may restore microbe-killing activities through nonoxidative mechanisms. We have shown that intracellular killing and in vivo clearance of S. aureus, as well as resistance to S. aureus sepsis, were significantly increased in gp91phox and Olfm4 double-deficient mice compared with CGD mice. Activities of cathepsin C and its downstream proteases (neutrophil elastase and cathepsin G) and serum levels of IL1β, IL6, IL12 p40, CXCL2, G-CSF, and GM-CSF in Olfm4-deficient as well as gp91phox and Olfm4 double-deficient mice were significantly higher than those in WT as well as CGD mice after challenged with S. aureus. However, we did not observe enhanced defense against A. fumigatus in Olfm4-deficient mice using a lung-infection model. These results show that Olfm4 deletion can successfully enhance immune defense against S. aureus, but not A. fumigatus in CGD mice. To determine whether the effect of Olfm4 deletion on S. aureus immune defense is mediated through the TLR-MyD88 pathway, we investigated the host defense of MyD88 and Olfm4 double-deficient mice against S. aureus systemic infection. While the MyD88 deficient mice were highly susceptible to S. aureus infection, additional Olfm4 elimination remarkably improved the survival of MyD88-deficient mice and enhanced the serum levels of some NF-κB targeted pro-inflammatory cytokines and chemokines. These results suggest that enhanced mouse innate immunity due to Olfm4 deletion is TLR-MyD88 signal independent, and that NOD-mediated NF-κB may play an important role. Taken together, we found that deletion of Olfm4, a critical negative regulator of neutrophil protease activities and the NOD-mediated pathway, could enhance the immune defense against S. aureus infection in CGD mice. This finding provides a rationale to enhance CGD patient defense against bacterial infections potentially through the modulation of OLFM4 levels. OLFM4 might prove to be an important target in CGD patients to augment host defense against bacterial infection.