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Farnesoid X Receptor Regulates Immune Cell Activation and Recruitment to the Lung following Exposure of Mice to Nitrogen Mustard
Author(s) -
Banota Tanvi,
Murray Alexa,
Sowinski Amanda,
Kong Bo,
Guo Grace,
Laskin Jeffrey,
Laskin Debra
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03896
Subject(s) - farnesoid x receptor , immune system , lung , receptor , chemistry , microbiology and biotechnology , pharmacology , immunology , medicine , biology , nuclear receptor , biochemistry , transcription factor , gene
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. This is accompanied by a robust inflammatory cell response, including activation of resident alveolar macrophages and an accumulation of bone marrow‐derived monocytes in the lung, which develop into pro‐inflammatory/cytotoxic M1 macrophages and anti‐inflammatory/pro‐fibrotic M2 macrophages. Farnesoid X receptor (FXR) is a bile‐acid activated nuclear receptor involved in lipid homeostasis; it has also been shown to exert anti‐inflammatory activity. In previous studies we showed that expression of FXR, along with two of its targets, ApoA and ApoE, were upregulated in lung macrophages following NM exposure. In these studies, we analyzed the role of FXR in regulating macrophage accumulation and activation in the lung following NM exposure. Male and female wild type (WT) and FXR ‐/‐ mice were treated with PBS (control) or NM (0.08 mg/kg) via intratracheal instillation. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected 3, 14, and 28 days later. NM caused histopathologic alterations in the lung including inflammatory cell infiltration, septal damage, and epithelial thickening, which were more prominent in FXR ‐/‐ mice relative to WT mice at all post exposure time points. This correlated with aggravated increases in BAL protein and cell content. Flow cytometric analysis revealed that both pro‐ and anti‐inflammatory macrophages accumulate in the lung following NM exposure. Pro‐inflammatory macrophages were most abundant in BAL 3 days post NM, a response more pronounced in FXR ‐/‐ mice. In male but not female mice, increases in proinflammatory macrophages persisted in the lung for at least 28 d post NM. In contrast, while anti‐inflammatory macrophages also increased in the lung following NM administration, no differences were observed between WT and FXR ‐/‐ mice. These findings demonstrate that FXR modulates proinflammatory macrophage responses to NM in a sex‐dependent manner and suggest a potential new target for the development of therapeutics to blunt mustard vesicant induced lung inflammation and injury.