C-type lectin receptor Clec4d plays a protective role in resolution of Gram-negative pneumonia

Abstract

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.

C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

“…This suggests that MCL potentially contributes to immunity against all pathogens that are recognized by Mincle, such as fungi and bacteria as well as mycobacteria (3,14,19,26), although we cannot exclude Mincleindependent MCL function. In line with this idea, MCL-deficient mice show high susceptibility to infection by Klebsiella pneumonia, Candida albicans, and Mycobacterium bovis bacillus CalmetteGuérin (6,16,27), all of which are reported to be poorly eliminated in Mincle-deficient mice (5,26,28). As Mincle also recognizes dead cells (18) as well as microorganisms, MCL may also participate in inflammatory responses against damaged tissue.…”

Distinct Contributions of Neutrophils and CCR2+Monocytes to Pulmonary Clearance of Different Klebsiella pneumoniae Strains

“…Along similar lines, mice lacking MyD88, TRIF, interleukin-1 receptor (IL-1R), Toll-like receptor 4 (TLR4), and leukotriene B 4 (LTB4) had reduced neutrophil recruitment and reduced resistance to K. pneumoniae 43816 infection, but the impact of these deficiencies on inflammatory monocyte recruitment remains unclear (6,(9)(10)(11). In other cases, such as deficiency of the C-type lectin receptors Clec4E and Clec4D, resistance to K. pneumoniae infection was reduced but neutrophil recruitment to the lung was increased (12,13). The demonstration that IL-17R deficiency increases susceptibility to K. pneumoniae infection further supports the potential role of neutrophils in bacterial clearance (14).…”

The C-Type Lectin Receptor MCL Mediates Vaccine-Induced Immunity against Infection with Blastomyces dermatitidis

“…Consequently, MCL is critically involved in TDM-induced experimental autoimmune encephalomyelitis (EAE) (15) and plays a nonredundant role in antimycobacterial innate immunity (17). MCL also has been shown to play a protective role in innate host defense against Gram-negative pneumonia (22). Aside from studies with C. albicans and Fonsecaea pedrosoi (13,23), the role of MCL in antifungal immunity remains poorly defined.…”