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Neutrophils Facilitate Prolonged Inflammasome Response in the DAMP-Rich Inflammatory Milieu

Authors
 Seunghwan Son  ;  Sung-Hyun Yoon  ;  Byeong Jun Chae  ;  Inhwa Hwang  ;  Do-Wan Shim  ;  Young Ho Choe  ;  Young-Min Hyun  ;  Je-Wook Yu 
Citation
 FRONTIERS IN IMMUNOLOGY, Vol.12 : 746032, 2021-09 
Journal Title
FRONTIERS IN IMMUNOLOGY
Issue Date
2021-09
Keywords
DAMP ; NLRP3 desensitization ; SARM1 ; efferocytosis ; inflammasome ; neutrophil ; pyroptosis
Abstract
Aberrant inflammasome activation contributes to various chronic inflammatory diseases; however, pyroptosis of inflammasome-active cells promptly terminates local inflammasome response. Molecular mechanisms underlying prolonged inflammasome signaling thus require further elucidation. Here, we report that neutrophil-specific resistance to pyroptosis and NLRP3 desensitization can facilitate sustained inflammasome response and interleukin-1β secretion. Unlike macrophages, inflammasome-activated neutrophils did not undergo pyroptosis, indicated by using in vitro cell-based assay and in vivo mouse model. Intriguingly, danger-associated molecular patterns (DAMP)-rich milieu in the inflammatory region significantly abrogated NLRP3-activating potential of macrophages, but not of neutrophils. This macrophage-specific NLRP3 desensitization was associated with DAMP-induced mitochondrial depolarization that was not observed in neutrophils due to a lack of SARM1 expression. Indeed, valinomycin-induced compulsory mitochondrial depolarization in neutrophils restored inflammasome-dependent cell death and ATP-induced NLRP3 desensitization in neutrophils. Alongside prolonged inflammasome-activating potential, neutrophils predominantly secreted interleukin-1β rather than other proinflammatory cytokines upon NLRP3 stimulation. Furthermore, inflammasome-activated neutrophils did not trigger efferocytosis-mediated M2 macrophage polarization essential for the initiation of inflammation resolution. Taken together, our results indicate that neutrophils can prolong inflammasome response via mitochondria-dependent resistance to NLRP3 desensitization and function as major interleukin-1β-secreting cells in DAMP-rich inflammatory region.
DOI
10.3389/fimmu.2021.746032
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Others (기타) > 1. Journal Papers
Yonsei Authors
Shim, Do-Wan(심도완)
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
Hyun, Young-Min(현영민) ORCID logo https://orcid.org/0000-0002-0567-2039
Hwang, Inhwa(황인화) ORCID logo https://orcid.org/0000-0001-5235-3519
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/185982
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