Ozone-derived oxysterols impair lung macrophage phagocytosis via adduction of some phagocytosis receptors

Abstract

Inhalation of the ambient air pollutant ozone causes lung inflammation and can suppress host defense mechanisms, including impairing macrophage phagocytosis. Ozone reacts with cholesterol in the lung to form oxysterols, like secosterol A and secosterol B (SecoA and SecoB), which can form covalent adducts on cellular proteins. How oxysterol-protein adduction modifies the function of lung macrophages is unknown. Herein, we used a proteomic screen to identify lung macrophage proteins that form adducts with ozone-derived oxysterols. Functional ontology analysis of the “adductome” indicated that protein binding was a major function of adducted proteins. Further analysis of specific proteins forming adducts with SecoA identified the phagocytic receptors CD206 and CD64. Adduction of these receptors with ozone-derived oxysterols impaired ligand binding and corresponded with reduced macrophage phagocytosis. This work suggests a novel mechanism for the suppression of macrophage phagocytosis following ozone exposure through the generation of oxysterols and the formation of oxysterol-protein adducts on phagocytic receptors.

Carnosine Stimulates Macrophage-Mediated Clearance of Senescent Skin Cells Through Activation of the AKT2 Signaling Pathway by CD36 and RAGE

“…Treatment of macrophages with carnosine at 5, 10 and 30 mM for 24 h did not exert any significant cytotoxicity on the cells (data not shown). Macrophages express a variety of receptors involved in cell recognition and engulfment, including CD14, CD36, CD44, CD206, TLR2, TLR4 and RAGE (Hazen, 2008;Hart et al, 2012;Lee et al, 2018;Lu and Chen, 2019;Mohammadi et al, 2019;Duffney et al, 2020;Lee et al, 2020). After pretreatment of the macrophages with 30 mM carnosine for 0, 3, 6, 12 and 24 h, the levels of CD36 and RAGE mRNAs were significantly increased at 12 and 24 h, respectively, after the treatment ( Figure 4A).…”

Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid

“…Nuclear receptors, such as FXR, are emerging as major regulators of lipid homeostasis in the lung, playing a role in both physiological and pathological processes. Exposure to pulmonary toxicants can dysregulate nuclear receptor function resulting in altered lipid homeostasis and immune cell activation in the lung (Duffney et al 2020;Francis et al 2020;Shichino et al 2019). Elucidating mechanisms underlying impaired activity of FXR and other nuclear receptors following exposure to pulmonary toxicants, including NM as well as SM, may lead to the development of more specific therapeutics to treat diseases associated with aberrant lipid handling and inflammation.…”

PER2/P65-driven glycogen synthase 1 transcription in macrophages modulates gut inflammation and pathogenesis of rectal prolapse

“…The phagocytic capacity of BMDM in young and old mice was compared to characterize the decreased clearance of Streptococcus pneumoniae in old mice ( 48 ). The phagocytic ability of mouse macrophage-like cells was used to evaluate the clearance ability of macrophages in heart and lung tissues ( 49 , 50 ). In prolapsed Per2 −/− mice, impaired pathogen clearance of macrophages results in an increase in T cells, which in turn leads to the production of proinflammatory cytokines and the development of inflammation.…”