Department of Microbiology and Immunology, The University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202-9037, USA.
J Leukoc Biol. 2013 Sep;94(3):393-8. doi: 10.1189/jlb.1212622. Epub 2013 May 24.
Pneumonia is frequently associated with sepsis, characterized by a nonresolving hyperinflammation. However, specific host components of the pulmonary milieu that regulate the perpetuation of inflammation and tissue destruction observed in this immune disorder are not clearly understood. We examined the function of Clec4d, an orphan mammalian CLR, in Gram negative pneumonic sepsis caused by KPn. Whereas the WT mice infected with a sublethal dose of bacteria could resolve the infection, the Clec4d(-/-) mice were highly susceptible with a progressive increase in bacterial burden, hyperinflammatory response typical of sepsis, and severe lung pathology. This correlated with a massive accumulation of neutrophils in lungs of infected Clec4d(-/-) mice, which was in contrast with their WT counterparts, where neutrophils transiently infiltrated the lungs. Interestingly, the Clec4d(-/-) neutrophils did not exhibit any defect in bacterial clearance. These results suggest that Clec4d plays an important role in resolution of inflammation, possibly by facilitating neutrophil turnover in lungs. This is the first report depicting the physiological function of Clec4d in a pathological condition. The results can have implications not only in sepsis but also in other inflammatory diseases, where nonresolving inflammation is the root cause of disease development.
肺炎常伴有脓毒症，其特征是持续存在的过度炎症。然而，在这种免疫紊乱中，调节炎症和组织破坏持续存在的肺部环境中的特定宿主成分尚不清楚。我们研究了 Clec4d（一种孤儿哺乳动物 CLR）在由 KPn 引起的革兰氏阴性肺炎性脓毒症中的功能。虽然 WT 小鼠感染了低致死剂量的细菌可以消除感染，但 Clec4d(-/-) 小鼠极易感染，细菌负荷持续增加，出现脓毒症的典型过度炎症反应和严重的肺部病理。这与感染 Clec4d(-/-) 小鼠肺部大量中性粒细胞积聚相关，而 WT 小鼠的中性粒细胞则短暂浸润肺部。有趣的是，Clec4d(-/-) 中性粒细胞在清除细菌方面没有任何缺陷。这些结果表明 Clec4d 在炎症消退中发挥重要作用，可能通过促进肺部中性粒细胞的更新来实现。这是首次在病理条件下描述 Clec4d 的生理功能。这些结果不仅对脓毒症，而且对其他炎症性疾病都具有重要意义，因为持续存在的炎症是疾病发展的根源。
