Fig. 1

Schematic representation of mechanisms putatively influencing rheumatoid arthritis through air pollution exposure. Four main mechanistic pathways are represented (blue, brown, red, and green arrows). Blue arrows: free reactive oxygen species released by fine/ultrafine particulate matter (PM) inhaled in the respiratory activate nuclear factor ƙappa B (NF-ƙB) that stimulates the production of tumor necrosis factor alpha (TNF-α), interleukin 1 (IL1) and interleukin 6 (IL6) by T helper lymphocytes type 1 (Th1). These cytokines stimulate resting monocytes to mature dendritic cells which then present autoantigens, co-stimulating self-reactive T lymphocytes that migrate to target tissues (preferentially synovial joints), and cause destruction of cells expressing autoantigens and thereby joint inflammation and erosion. Brown arrows: free reactive oxygen species cause chronic lung and systemic inflammation that enhance citrullination of arginine amino acid residues into citrullinated proteins/peptides. These citrullinated products induce anticyclic citrullinated protein/peptide antibodies (ACPAs) production that will later on lead to immune reaction through binding to cellular Fc receptors and complement activation, and finally cause joint inflammation and erosion. Red arrow: reactive oxygen species per se can worsen joint inflammation and erosion. Green arrows: Reduced ultraviolet B (UVB) radiation levels lead to decreased skin synthesis of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] which acts as an immunomodulator through vitamin D receptor (VDR) activation. Resultantly, immunomodulatory activities of 1,25(OH)₂D₃ represented by green doted arrows are not met, and RA can develop. IFN-γ interferon gamma; NK natural killer cells; and Treg T regulatory cells