Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: Role in posthemorrhagic shock acute lung inflammation

Zongmei Wen, Liyan Fan, Yuehua Li, Zui Zou, Melanie J. Scott, Guozhi Xiao, Song Li, Timothy R. Billiar, Mark A. Wilson, Xueyin Shi, Jie Fan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome after hemorrhagic shock (HS) resulting from major surgery and trauma. The increased susceptibility in HS patients to the development of ALI suggests not yet fully elucidated mechanisms that enhance proinflammatory responses and/or suppress anti-inflammatory responses in the lung. Alveolar macrophages (AMπ) are at the center of the pathogenesis of ALI after HS. We have previously reported that HS-activated polymorphonuclear neutrophils (PMNs) interact with macrophages to influence inflammation progress. In this study, we explore a novel function of PMNs regulating AMf anti-inflammatory mechanisms involving autophagy. Using a mouse "two-hit" model of HS/resuscitation followed by intratracheal injection of muramyl dipeptide, we demonstrate that HS initiates high mobility group box 1/TLR4 signaling, which upregulates NOD2 expression in AMπ and sensitizes them to subsequent NOD2 ligand muramyl dipeptide to augment lung inflammation. In addition, upregulated NOD2 signaling induces autophagy in AMπ, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. Importantly, we further demonstrate that HS-activated PMNs that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AMπ, possibly through NAD(P)H oxidase-mediated signaling to enhance I-κB kinase γ phosphorylation, NF-κB activation, and nucleotide-binding oligomerization domain protein 3 inflammasome activation, and therefore augment post-HS lung inflammation. These findings explore a previously unidentified complexity in the mechanisms of ALI, which involves cell-cell interaction and receptor cross talk.

Original languageEnglish
Pages (from-to)4623-4633
Number of pages11
JournalJournal of Immunology
Volume193
Issue number9
DOIs
StatePublished - 1 Nov 2014
Externally publishedYes

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