Blocking interleukin 33 reduces joint, systemic, and lung inflammatory responses in the combined collagen-induced arthritis-inhalant endotoxin exposure model.

Therapies capable of resolving rheumatoid arthritis (RA)-associated lung disease, particularly in the setting of environmental exposures, are lacking. This study sought to determine whether blocking interleukin (IL)-33 in a murine model of RA-associated lung disease induced by combined collagen-induced arthritis (CIA) and repeated inhalant lipopolysaccharide (LPS) exposures could be advantageous. Arthritis prone male DBA/1J mice received CIA (vs saline) injections (days 1 and 21) plus intranasal LPS (100 ng) or saline daily for 4 weeks and were subsequently treated with 5 doses of anti-IL-33 (10 mg/kg) or isotype over 11 days. Anti-IL-33 therapy significantly (P < .05) mitigated several CIA+LPS-induced effects. Anti-IL-33 reduced arthritis inflammatory score by 76% and serum acute phase reactant pentraxin-2 by 70% and reversed weight loss induced by CIA+LPS coexposure. Anti-IL-33 reduced CIA+LPS-induced antimalondialdehyde acetaldehyde but not anticitrullinated autoantibodies in serum and reduced serum levels of inflammatory mediators. Lung cell infiltrates induced by coexposure, including neutrophils, activated lung macrophages, transitional monocytes-macrophages, monocytic-like cells, and dendritic cells, were reduced with anti-IL-33. Anti-IL-33 also reduced CIA+LPS-induced lung levels of chemokines involved in monocyte-macrophage recruitment and fibrotic/repair mediators collagen deposition, IL-33 expression, inflammatory CC motif chemokine receptor 2+ monocytes/macrophages, and airway Muc5b immunostaining induced by CIA+LPS were reduced with anti-IL-33. CIA+LPS-induced lung expression of post-translational modified autoantigens including citrullinated and malondialdehyde acetaldehyde and its common substrate, vimentin, was reduced with anti-IL-33 treatment. Blocking IL-33 was beneficial in hastening lung recovery after establishment of disease by coexposure to CIA+LPS and potentially represents a novel therapeutic approach in RA-associated lung disease. SIGNIFICANCE STATEMENT: Blocking the interleukin (IL)-33 signaling pathway after the establishment of, but not during the induction of, rheumatoid arthritis (RA)-associated lung disease, as modeled by coexposure of collagen-induced arthritis with repetitive inhalant endotoxin, demonstrated beneficial consequences in reducing inflammatory joint, systemic, and lung disease. Treatment with anti-IL-33 agents, particularly in men with a history of environmental exposures, may represent a novel approach to reduce disease burden in humans with established RA-lung disease, underscoring an important role for the IL-33 pathway.