title: Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation.
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 (AMϕ) 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 AMϕ 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 AMϕ and sensitizes them to subsequent NOD2 ligand muramyl dipeptide to augment lung inflammation. In addition, 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 PMNs that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AMϕ, 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.
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Zongmei
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Department of Biological Sciences, University of Pittsburgh School of Arts and Sciences, Pittsburgh, PA 15213;
authors.forename: Liyan
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China;
authors.forename: Zui
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612;
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261;
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219; and.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; jif7@pitt.edu shixueyin1128@163.com.
authors.forename: Xueyin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219; and Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240 jif7@pitt.edu shixueyin1128@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000473:pathology; D000818:Animals; D001343:Autophagy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D024243:HMGB1 Protein / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000150:complications; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D058847:Inflammasomes; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D051197:Toll-Like Receptor 4; D019255:NADPH Oxidases