A significant number of chronic inflammatory and metabolic diseases have recently been identified to have inflammasome-mediated inflammation as a key driver of their pathogenesis this area of research is under intense investigation at present. Inflammasomes are sensors within the innate immune system that are responsible for the regulation of caspase-1 activation and the initiation of inflammatory responses following cellular infection or damage. In this manuscript, we reviewed the effects of silica on macrophage mitochondrial respiration and central carbon metabolism determining cytokine specification responsible for the sustained inflammatory responses in the lungs. In contrast to bacteria, silica particles cannot be degraded, and the persistent macrophage activation results in an increased NADPH oxidase (Phox) activation and mitochondrial reactive oxygen species (ROS) production, ultimately leading to macrophage death and release of silica particles that perpetuate inflammation. Silica-stimulated macrophages activate pattern recognition receptors (PRRs) and NLRP3 inflammasome and release IL-1β, TNF-α, and interferons, which are the key mediators of silicosis pathogenesis. In contrast to LPS, the nature of the immunometabolic responses induced by non-organic particles, such as silica, in macrophages, its contribution to cytokine specification, and disease pathogenesis are not well understood. Glycolysis suppression using 2 deoxyglucose in LPS-stimulated macrophages inhibits IL-1β secretion, but not TNF-α, indicating metabolic pathway specificity that determines cytokine production. Lipopolysaccharide (LPS)-stimulated macrophages demonstrate enhanced glycolysis, blocked succinate dehydrogenase (SDH), and increased secretion of interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Activated macrophages show altered immunometabolism and metabolic changes governing immune effector mechanisms, such as cytokine secretion characterizing their classic (M1) or alternative (M2) activation. In the lungs, macrophages constitute the first line of defense against pathogens and foreign bodies and play a fundamental role in maintaining tissue homeostasis. Data (error bars, s.d.) are from one representative experiment of two (c,d,f–h) or three (b,e). (h) ELISA of IL-1 production by LPS-primed bone marrow–derived macrophages treated for 6 h with alum or MSU crystals in the presence of increasing doses of uricase, presented as the percent of the maximum (100%) obtained in the absence of uricase. (g) ELISA of the release of IL-1 by LPS-primed bone marrow–derived macrophages left untreated or treated with the cathepsin B inhibitor CA-074-Me (10 M) or bafilomycin (250 nM) and then stimulated with alum. (d–f) Confocal microscopy of wild-type macrophages incubated for 60 min with DQ ovalbumin (10 g/ml red) alone or together with alum (green) and then stained with fluorescent cholera toxin B-subunit (blue d) or stained with acridine orange and then treated with alum (blue e) or left untreated (right) or incubated for 3 h with alum (pink left), then stained for 1 h with fluorescent probes for activated caspase-1 (green) and activated cathepsin B (red) and then surface-stained with fluorescent cholera toxin B-subunit (blue f). (c) Flow cytometry of neutrophils in peritoneal lavage fluid from wild-type mice (n = 5) and IL1R-deficient mice (n = 5) given peritoneal injection of alum (100 ug) or PBS 16–18 h before. (b) ELISA of IL-1 in supernatants of wild-type, NALP3-deficient or ASC-deficient bone marrow–derived macrophages primed for 3 h with LPS and then stimulated with alum (500 g/ml). Results are from four donors (ELISA) or one representative donor (immunoblot). Each dot above a lane represents one donor small horizontal lines indicate the mean. Alum activates the NALP3 inflammasome through lysosomal destabilization.(a) ELISA (above supernatants) and immunoblot analysis (below) of IL-1 production by human PBMCs left untreated or primed for 3 h with LPS (25 pg/ml) and then stimulated for 6 h with increasing doses of alum.
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