Biological mechanisms of pulmonary inflammation and its association with seropositive rheumatoid arthritis

Abstract

Although the pathogenesis of seropositive rheumatoid arthritis (RA) remains unclear, studies suggest that pulmonary inflammation-related biological mechanisms play a significant role in its development. This review thoroughly explores the mechanisms underlying early pulmonary lesions in seropositive RA, focusing on the mucosal barrier hypothesis, neutrophil extracellular traps, pathogenic microbial infections like COVID-19, Vitamin D, the microbiome and gut-lung axis, inhalation exposures and chronic pulmonary diseases. This study seeks to provide novel insights and theoretical foundations for the prevention and treatment of seropositive rheumatoid arthritis.

Keywords: COVID-19; anti-citrullinated protein antibodies; gut-lung axis; pulmonary inflammation; rheumatoid arthritis.

Figure 1

The vicious cycle in the lungs of seropositive rheumatoid arthritis patients. Inflammation triggers the NF-κB signaling pathway via pathogen-associated molecular pattern (PAMP) or damage-associated molecular pattern (DAMP) receptors, leading to the expression of NLRP3 and IL-1β. NLRP3 proteins assemble into the NLRP3 inflammasome complex, activating caspase-1 to trigger pyroptosis and facilitate the maturation of IL-1β and IL-18, thereby initiating downstream immune responses. The NLRP3-mediated inflammatory response can ultimately promote B cell proliferation and antibody production as well as T cell proliferation, differentiation, and cytokine release. ACPA enhances the expression of NLRP3 and IL-1β. This abnormal activation may create a vicious cycle in the lungs of seropositive RA patients and potentially lead to a cytokine storm.

Figure 2

Formation and dissemination of anti-citrullinated protein antibodies in the lungs. Chronic pulmonary inflammation causes cellular damage and apoptosis, releasing significant calcium ions that activate PAD. PAD facilitates the transformation of protein arginine residues into citrulline, which disrupts immune tolerance, and triggers a specific immune response, resulting in ACPA production. The loss of mucosal barrier integrity caused by pulmonary inflammation further facilitates the leakage of abnormally produced ACPA into systemic circulation.