Centrality of Myeloid-Lineage Phagocytes in Particle-Triggered Inflammation and Autoimmunity

Abstract

Exposure to exogenous particles found as airborne contaminants or endogenous particles that form by crystallization of certain nutrients can activate inflammatory pathways and potentially accelerate autoimmunity onset and progression in genetically predisposed individuals. The first line of innate immunological defense against particles are myeloid-lineage phagocytes, namely macrophages and neutrophils, which recognize/internalize the particles, release inflammatory mediators, undergo programmed/unprogrammed death, and recruit/activate other leukocytes to clear the particles and resolve inflammation. However, immunogenic cell death and release of damage-associated molecules, collectively referred to as “danger signals,” coupled with failure to efficiently clear dead/dying cells, can elicit unresolved inflammation, accumulation of self-antigens, and adaptive leukocyte recruitment/activation. Collectively, these events can promote loss of immunological self-tolerance and onset/progression of autoimmunity. This review discusses critical molecular mechanisms by which exogenous particles (i.e., silica, asbestos, carbon nanotubes, titanium dioxide, aluminum-containing salts) and endogenous particles (i.e., monosodium urate, cholesterol crystals, calcium-containing salts) may promote unresolved inflammation and autoimmunity by inducing toxic responses in myeloid-lineage phagocytes with emphases on inflammasome activation and necrotic and programmed cell death pathways. A prototypical example is occupational exposure to respirable crystalline silica, which is etiologically linked to systemic lupus erythematosus (SLE) and other human autoimmune diseases. Importantly, airway instillation of SLE-prone mice with crystalline silica elicits severe pulmonary pathology involving accumulation of particle-laden alveolar macrophages, dying and dead cells, nuclear and cytoplasmic debris, and neutrophilic inflammation that drive cytokine, chemokine, and interferon-regulated gene expression. Silica-induced immunogenic cell death and danger signal release triggers accumulation of T and B cells, along with IgG-secreting plasma cells, indicative of ectopic lymphoid tissue neogenesis, and broad-spectrum autoantibody production in the lung. These events drive early autoimmunity onset and accelerate end-stage autoimmune glomerulonephritis. Intriguingly, dietary supplementation with ω-3 fatty acids have been demonstrated to be an intervention against silica-triggered murine autoimmunity. Taken together, further insight into how particles drive immunogenic cell death and danger signaling in myeloid-lineage phagocytes and how these responses are influenced by the genome will be essential for identification of novel interventions for preventing and treating inflammatory and autoimmune diseases associated with these agents.

The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data

“…In addition, the so-called “tolerance” of cells secreting cytokines contributes to the completion of the inflammatory reaction. Tolerance is manifested in the fact that, with repeated pro-inflammatory stimulation of cells, the secretion of cytokines is significantly reduced compared to the first stimulation [ 17 , 18 , 19 ]. Naturally, chronification of inflammation occurs when the inflammation resolution mechanisms are violated.…”

Dietary docosahexaenoic acid supplementation inhibits acute pulmonary transcriptional and autoantibody responses to a single crystalline silica exposure in lupus-prone mice

“…Acting as initial responders to inhaled foreign particles, AM phagocytose inhaled cSiO 2 , leading to: 1) release of IL-1α and IL-1β, driving cytokine/chemokine production and myeloid/lymphoid cell recruitment; 2) necroptosis, apoptosis, and pyroptosis, releasing cSiO 2 for further uptake; and 3) sequestration and gradual clearance via the mucociliary escalator ( 29 , 30 ) ( Figure 12 ). In lupus-prone mice, uncleared cell corpses undergo secondary necrosis, releasing DAMPs and autoantigens (AAgs).…”

Cystic fibrosis autoantibody signatures associate with Staphylococcus aureus lung infection or cystic fibrosis-related diabetes

“…CF lung disease pathogenesis has been classically characterized as the triad of decreased mucociliary clearance, neutrophil-dominated inflammation and polymicrobial infections. Chronic inflammation and infections are also known to increase the chance for the development of autoimmunity in several conditions ( 16 – 18 ). While CF has not been considered traditionally as an autoimmune disease, we thought that the circumstances are present for its potential development in CF.…”