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Helminth resistance is mediated by differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion.

ABSTRACT: Macrophages are known to mediate anti-helminth responses, but it remains uncertain which subsets are involved or how macrophages actually kill helminths. Here, we show rapid monocyte recruitment to the lung after infection with the nematode parasite Nippostrongylus brasiliensis. In this inflamed tissue microenvironment, these monocytes differentiate into an alveolar macrophage (AM)-like phenotype, expressing both SiglecF and CD11c, surround invading parasitic larvae, and preferentially kill parasites in vitro. Monocyte-derived AMs (Mo-AMs) express type 2-associated markers and show a distinct remodeling of the chromatin landscape relative to tissue-derived AMs (TD-AMs). In particular, they express high amounts of arginase-1 (Arg1), which we demonstrate mediates helminth killing through L-arginine depletion. These studies indicate that recruited monocytes are selectively programmed in the pulmonary environment to express AM markers and an anti-helminth phenotype.

SUBMITTER: Chen F

PROVIDER: S-EPMC9403845 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Helminth resistance is mediated by differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion.

Chen Fei F El-Naccache Darine W DW Ponessa John J JJ Lemenze Alexander A Espinosa Vanessa V Wu Wenhui W Lothstein Katherine K Jin Linhua L Antao Olivia O Weinstein Jason S JS Damani-Yokota Payal P Khanna Kamal K Murray Peter J PJ Rivera Amariliz A Siracusa Mark C MC Gause William C WC

Cell reports 20220101 2

Macrophages are known to mediate anti-helminth responses, but it remains uncertain which subsets are involved or how macrophages actually kill helminths. Here, we show rapid monocyte recruitment to the lung after infection with the nematode parasite Nippostrongylus brasiliensis. In this inflamed tissue microenvironment, these monocytes differentiate into an alveolar macrophage (AM)-like phenotype, expressing both SiglecF and CD11c, surround invading parasitic larvae, and preferentially kill para ...[more]

PMID: 35021079

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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.

Dataset Information

Helminth resistance is mediated by differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion.

Publications

Helminth resistance is mediated by differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion.

Similar Datasets

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