4.8 Article

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

Journal

FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.746032

Keywords

neutrophil; inflammasome; pyroptosis; DAMP; NLRP3 desensitization; SARM1; efferocytosis

Categories

Funding

  1. National Research Foundation of Korea Grant - Korean Government [2017R1A 2B2007467, 2020R1A2B5B02001823, 2020R1A4A1019009]
  2. Dongwha Faculty Research Assistance Program of Yonsei University College of Medicine [6-2019-0122]
  3. National Research Foundation of Korea [2020R1A4A1019009, 2020R1A2B5B02001823] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Neutrophils can prolong inflammasome response via mitochondria-dependent resistance to NLRP3 desensitization and function as major interleukin-1 beta-secreting cells in DAMP-rich inflammatory region. This resistance allows inflammasome-activated neutrophils to avoid pyroptosis, leading to sustained inflammasome response and interleukin-1 beta secretion. The unique mitochondrial characteristics in neutrophils, such as the lack of SARM1 expression, contribute to their resistance to NLRP3 desensitization and prolonged inflammasome activation potential.
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-1 beta 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-1 beta 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-1 beta-secreting cells in DAMP-rich inflammatory region.

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