GLUCOCORTICOID AND OMEGA-3 FATTY ACID INTERVENTIONS IN ENVIRONMENTAL TRIGGERED INFLAMMATION AND AUTOIMMUNE DISEASE

Systemic lupus erythematosus (lupus) is a chronic, debilitating autoimmune disease that predominantly afflicts women of childbearing age and women of color. While genetics plays a critical role in disease onset, environmental exposures to respirable toxicants such as crystalline silica (cSiO2) or Gram-negative bacterial lipopolysaccharide (LPS) have been implicated as triggers for lupus. Pre-clinical studies using lupus-prone mice have shown that pulmonary exposure to cSiO2 leads to unresolved inflammation in the lung, which serves as a nexus for systemic autoimmunity. Similar to what has been observed in human patients, respirable toxicant exposures in lupus-prone mice results in recruitment of auto-reactive B- and T-cells, production of autoantibodies (AAb) and Type-I Interferons (IFNs), and development of glomerulonephritis. Currently, there is no cure for lupus and one of the mainstay treatments is glucocorticoids (GCs). While GCs help quell chronic inflammation, long-term use is associated with many adverse side effects. Interestingly, previous studies from the Pestka lab have shown that dietary supplementation with the omega-3 polyunsaturated fatty acid (PUFA), docosahexaenoic acid (DHA), attenuates cSiO2-triggered autoimmunity and improves survivability in lupus-prone mice. Additionally, DHA treatment in a novel alveolar-like macrophage cell line hinders LPS-primed pro-inflammatory and Type-I IFN transcriptional responses. Given the promising anti-inflammatory nature of DHA, this thesis builds upon previous in vivo and in vitro models to address the overarching hypothesis that DHA has steroid-sparing properties which can be harnessed to lower requisite doses of GCs needed to attenuate environmental triggered inflammation and autoimmunity. In this dissertation, four aims were employed to uncover how inflammation and autoimmunity are altered based on therapeutic intervention, age, and environmental stimuli. In the first aim, thresholds were determined for the GC prednisone’s immunomodulatory effects on cSiO2-triggered autoimmunity and secondary toxicity in NZBWF1 lupus-prone mice. A reduction in cSiO2-induced inflammation and autoimmunity was observed at a moderate relevant human equivalent dose (HED) of prednisone. Yet, at this same dose, GC-induced toxicity was observed and there was no improved survivability in cSiO2-exposed mice. In the second aim, age was addressed as contributing factor in cSiO2-induced autoimmunity in NZBWF1 lupus-prone mice. When using adult mice that more appropriately model the age of cSiO2-exposed workers, we observed that cSiO2 exposure resulted in intensified pulmonary inflammation compared to what has been observed in published studies using juvenile mice. In the third aim, environmentally triggered autoimmunity in NZBWF1 lupus-prone mice was assessed using another relevant environmental toxicant, LPS. Here, it was demonstrated that repeated administration of LPS resulted in local unresolved inflammation and systemic autoimmunity in a route of exposure-dependent manner. Lastly, in the fourth aim, the steroid-sparing potential of DHA was assessed in a novel alveolar-like macrophage cell line. In this study, LPS-stimulated proinflammatory and IFN transcriptional responses were reduced upon combination treatment with sub-optimal concentrations of DHA and the GC dexamethasone. Combination treatment was more effective in reducing LPS-induced responses compared to individual treatment with either DHA or the GC alone. Taken together, each of the present studies has provided novel insights into how therapeutics (e.g., GC and DHA), age, and unique environmental triggers influence inflammation and autoimmunity. Furthermore, these studies demonstrate DHA has the potential to be used as a steroid-sparing adjunct therapy to attenuate environmental-triggered lupus.