Neutrophils Counteract Autophagy-Mediated Anti-Inflammatory Mechanisms in Alveolar Macrophage: Role in Post-Hemorrhagic Shock Acute Lung Inflammation

摘要

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following 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 pro-inflammatory responses and/or suppress anti-inflammatory responses in the lung. Alveolar macrophages (AMϕ) are at the center of the pathogenesis of ALI after HS. We have previously reported that HS-activated polymorphonuclear neutrophils (PMN) interact with macrophages to influence inflammation progress. In this study, we explore a novel function of PMN regulating AMϕ anti-inflammatory mechanisms involving autophagy. Using a mouse “two-hit” model of HS/resuscitation followed by intratracheal injection of muramyl dipeptide (MDP), we demonstrate that HS initiates high mobility group box 1 (HMGB1)/TLR4 signaling, which upregulates NOD2 expression in AMϕ and sensitizes them to subsequent NOD2 ligand MDP to augment lung inflammation. Additionally, upregulated NOD2 signaling induces autophagy in AMϕ, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. Importantly, we further demonstrate that HS-activated PMN that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AMϕ, possibly through NAD(P)H oxidase mediated signaling to enhance IKKγ phosphorylation, NF-κB activation, and NLRP3 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.