Role of alveolar macrophage in omega-3 fatty acid amelioration of silica-triggered autoimmunity

This research examines how the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) modulates alveolar macrophage responses to inhaled crystalline silica (cSiO2), a particle linked to silicosis, lung cancer, and systemic autoimmune disease. Recognizing that primary alveolar macrophages (AMs) are short-lived and difficult to obtain in sufficient numbers for in vitro studies, the investigators employed fetal liver-derived alveolar-like macrophages (FLAMs) as a self-renewing surrogate that phenotypically reflects primary lung AMs. The study tested delivery of 25 µM DHA, administered either as ethanolic suspensions or complexed with bovine serum albumin (BSA), and assessed effects on phospholipid fatty acid composition, oxylipin production, proinflammatory cytokine release, and cell death following exposure to cSiO2, with or without lipopolysaccharide (LPS) priming.

Methodologically, the team compared DHA delivery methods and found both ethanolic and BSA-complexed DHA effectively increased ω-3 PUFA content in phospholipids while decreasing the ω-6 PUFA arachidonic acid (ARA) and ω-9 oleic acid. FLAMs were treated with 25 µM DHA or ethanol vehicle for 24 hours, primed with LPS for 2 hours in select conditions, and then exposed to cSiO2 for 1.5 or 4 hours. Oxylipin production was profiled using targeted LC-MS lipidomics across 156 oxylipins, enabling detailed resolution of ARA-derived eicosanoids and DHA-derived docosanoids. Concurrent measurements assessed proinflammatory cytokines and cell viability.

Results demonstrate that cSiO2 exposure time-dependently triggered a broad ARA-derived eicosanoid response in unprimed and LPS-primed FLAMs, encompassing prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acids. This œeicosanoid storm was markedly suppressed in DHA-supplemented FLAMs, which instead produced DHA-derived docosanoids with potential pro-resolving functions. In LPS-primed FLAMs, cSiO2 elicited substantial release of IL-1α, IL-1β, and TNF-α at both 1.5 and 4 hours; DHA significantly inhibited these cytokine responses. Regarding cell death, DHA did not alter cSiO2-triggered death in unprimed FLAMs but modestly increased death in LPS-primed FLAMs.

These findings indicate that DHA incorporation into FLAM phospholipids reshapes the lipidome to favor ω-3-derived mediators over ARA-derived proinflammatory eicosanoids, attenuating both oxylipin-mediated inflammation and key proinflammatory cytokine release after silica exposure. The study positions FLAMs as a viable in vitro platform for investigating early toxicant-triggered lung inflammation and testing interventions, offering an approach to study mechanisms and potential therapeutic modulation without sole reliance on scarce primary AMs. By demonstrating DHA's capacity to quell silica-induced eicosanoid storms and reduce cytokine output, this work supports further exploration of DHA or related ω-3 PUFA strategies to counteract particle-triggered pulmonary inflammation and its downstream contributions to chronic lung disease and systemic autoimmunity.