Mincle regulates autophagy to control neutrophil extracellular trap formation

Abstract

Abstract “Neutrophil extracellular traps (NETs) constitute antimicrobial function of neutrophils but have also been linked to perpetuation of inflammation. Despite this evident physiological relevance, mechanistic understanding of NET formation is poor. In the current study we examined the mechanism by which Mincle, a C-type lectin receptor, regulates NET formation. We found that Mincle mediates NET formation in response to several activation stimuli in-vitro and in-vivo during pneumoseptic infection with Klebsiella pneumoniae, indicating its regulatory role in NET formation. Mechanistically, we show that attenuated NET formation in Mincle−/− neutrophils correlates with an impaired autophagy activation in-vitro and in-vivo, while reactive oxygen species (ROS) formation in these neutrophils remained intact. The requirement of autophagy in Mincle-mediated NET formation was further supported by exogenous treatment with autophagy inducer tamoxifen, which rescued the NET formation defect in Mincle−/− neutrophils. Our findings identify a previously unrecognized role of Mincle as a regulator of autophagy which mediates NET formation without affecting ROS generation. Our study addresses a major challenge in the field by positing this pathway to be targeted for modulation of NETs, while preserving ROS production, an important innate immune defense.”