Bacillus anthracis peptidoglycan (PGN) is a major component of the bacterial cell wall and a key pathogen associated molecular pattern contributing to anthrax pathology including coagulopathy in late stage disease. Lymphocyte apoptosis is an established phenomenon in bacterial sepsis, including fulminant anthrax. Clearance of apoptotic cells (efferocytosis) is thought to be mediated by tissue-resident macrophages (MF), modeled in vitro as M2-like MF. Circulating innate cells need serum opsonization of PGN for cellular activation, but opsonization requirements for human MF activation have not been reported. Herein, we tested the hypothesis that PGN requires human serum opsonization for MF activation and inhibits human M2-like MF efferocytosis of apoptotic human neutrophils. MF were differentiated in vitro with M-CSF and polarized to M2 phenotype with dexamethasone. Cytokine and soluble receptor levels were assessed by ELISA and Luminex assays. Cell surface markers and fraction of MF containing fluorescently-labeled apoptotic human neutrophils were assessed by flow cytometry. M2-like MF recognition of PGN was enhanced in the presence of human but not bovine serum, noted by increased secretion of TNF-a and IL-10 in PGN-treated culture supernatants. Efferocytosis, and cell surface expression of MerTK, Tyro3, Axl, αVβ5, CD36 and Tim-3, all pro-efferocytic receptors, was significantly downregulated by pre-treatment of MF with PGN. Increases in soluble pro-efferocytic receptors were detected in PGN-treated MF culture supernatants. We conclude that PGN impairs efferocytosis by human M2-like macrophages, likely by down-regulating the expression of cell surface receptors known to signal apoptotic cell engulfment. Supported by NIH (U19AI062629).
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