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Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

ABSTRACT: Resident-tissue macrophages (RTMs) arise from embryonic precursors^1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15^-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E₂ production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.

SUBMITTER: Pernet E

PROVIDER: S-EPMC9945843 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Pernet Erwan E Sun Sarah S Sarden Nicole N Gona Saideep S Nguyen Angela A Khan Nargis N Mawhinney Martin M Tran Kim A KA Chronopoulos Julia J Amberkar Dnyandeo D Sadeghi Mina M Grant Alexandre A Wali Shradha S Prevel Renaud R Ding Jun J Martin James G JG Thanabalasuriar Ajitha A Yipp Bryan G BG Barreiro Luis B LB Divangahi Maziar M

Nature 20230104 7948

Resident-tissue macrophages (RTMs) arise from embryonic precursors<sup>1,2</sup>, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15<sup>-/-</sup> mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the ...[more]

PMID: 36599368

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Project description:IntroductionAcute lung injury (ALI) and its subsequent progression to acute respiratory distress syndrome (ARDS) are severe respiratory conditions. They are marked by rapid lung function deterioration and extensive pulmonary inflammation, often resulting in critical patient outcomes. Alveolar macrophages (AMs) and monocyte-derived macrophages (MDMs) are two distinct subsets of lung macrophages present in the alveoli during ALI. Both are critical mediators of pulmonary inflammation. Our study examined the interplay between AMs and MDMs in the inflammatory environment of ALI/ARDS.MethodsMice were treated with lipopolysaccharide (LPS) to establish ALI models. The lung tissues of mice were subjected to hematoxylin-eosin staining to observe the degree of tissue damage. In vivo, CCR2-deficient mice or depleting peripheral blood mononuclear cells by clodronate liposomes were used to reduce MDMs recruitment. The bronchoalveolar lavage fluid (BALF) supernatants were used for cytokine and total protein analyses. AMs and MDMs in the BALF were analyzed by flow cytometry. The levels of AMs death were determined through propidium iodide staining and measured by flow cytometry. In vitro, primary AMs were exposed to MDM-conditioned medium or TNF-α, and their death levels were assessed under a fluorescence microscope with propidium iodide staining.ResultsAMs significantly decrease in number and undergo extensive cell death during ALI. The reduced MDMs recruitment can increase the number of AMs, reduce AMs death, and alleviate lung injury. In vitro, MDM-conditioned medium can induce AMs death and TNF-α is one of the major secretions. It indicates that TNF-α stimulation in vitro promotes AMs death. In vivo, MDMs are identified as the primary cells secreting TNF-α. Additionally, the treatment with TNF-α antagonists can reduce AMs death and the severity of lung injury.ConclusionOur study demonstrates that MDMs contribute to AMs death during ALI through TNF-α. Targeting TNF-α may offer a therapeutic strategy to mitigate AMs death and lung injury in ALI/ARDS.

Project description:Pulmonary fibrosis is a disease in which lung tissues become fibrous and thereby causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract, secreting inflammatory cytokines, which subsequently leads to the development of pulmonary fibrosis. Aesculetin, a major component of the sancho tree and chicory, is known to biologically have antioxidant and anti-inflammatory effects. Human alveolar epithelial A549 cells were cultured for 24 h in conditioned media of THP-1 monocyte-derived macrophages (mCM) with 1-20 ?M aesculetin. Micromolar aesculetin attenuated the cytotoxicity of mCM containing inflammatory tumor necrosis factor-? (TNF)-? and interleukin (IL)-8 as major cytokines. Aesculetin inhibited alveolar epithelial induction of the mesenchymal markers in mCM-exposed/IL-8-loaded A549 cells (?47-51% inhibition), while epithelial markers were induced in aesculetin-treated cells subject to mCM/IL-8 (?1.5-2.3-fold induction). Aesculetin added to mCM-stimulated A549 cells abrogated the collagen production and alveolar epithelial CXC-chemokine receptor 2 (CXCR2) induction. The production of matrix metalloproteinase (MMP) proteins in mCM-loaded A549 cells was reduced by aesculetin (?52% reduction), in parallel with its increase in tissue inhibitor of metalloproteinases (TIMP) proteins (?1.8-fold increase). In addition, aesculetin enhanced epithelial induction of tight junction proteins in mCM-/IL-8-exposed cells (?2.3-2.5-fold induction). The inhalation of polyhexamethylene guanidine (PHMG) in mice accompanied neutrophil predominance in bronchoalveolar lavage fluid (BALF) and macrophage infiltration in alveoli, which was inhibited by orally administrating aesculetin to mice. Treating aesculetin to mice alleviated PHMG-induced IL-8-mediated subepithelial fibrosis and airway barrier disruption. Taken together, aesculetin may antagonize pulmonary fibrosis and alveolar epithelial barrier disruption stimulated by the infiltration of monocyte-derived macrophages, which is typical of PHMG toxicity, involving interaction of IL-8 and CXCR2. Aesculetin maybe a promising agent counteracting macrophage-mediated inflammation-associated pulmonary disorders.

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Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Publications

Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

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