Mincle-mediated neutrophil extracellular trap formation by regulation of autophagy

Atul Sharma, Tanner J. Simonson, Christopher N. Jondle, Bibhuti B. Mishra, Jyotika Sharma

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Background. 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 this study, we examined the mechanism by which Mincle, a C-type lectin receptor, regulates NET formation. Methods. NET formation, reactive oxygen species, autophagy activation and intracellular signaling pathways were analyzed in Mincle-sufficient and -deficient neutrophils stimulated in vitro with various stimuli and in vivo during Klebsiella infection. Results. 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, whereas 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. Conclusions. 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.

Original languageEnglish (US)
Pages (from-to)1040-1048
Number of pages9
JournalJournal of Infectious Diseases
Volume215
Issue number7
DOIs
StatePublished - Apr 1 2017
Externally publishedYes

Keywords

  • Autophagy
  • Bacterial infection
  • Innate immune response
  • Klebsiella pneumoniae
  • Mincle
  • Neutrophil extracellular traps (NETs)
  • Pneumonia
  • Reactive oxygen species
  • Sepsis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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