Role of environmental toxins in chronic experimental arthrithis - in search for anti-inflammatory pathways of ethanol and nicotine

Abstract: Rheumatoid arthritis (RA) is a common systemic autoimmune disorder and a debilitating disease affecting 1% of the world population. The etiology of RA is an unresolved issue. Environmental factors such as alcohol intake and cigarette smoke have been described as contributing to the pathogenesis of RA. These assumptions are based on epidemiological studies, while experimental proof on this issue is limited. This thesis studies the effect of common environmental toxins on experimental arthritis induced by collagen type II (collagen-induced arthritis, CIA), an established murine model closely resembling human RA. We propose biological mechanisms behind the anti-inflammatory properties of environmental stimuli such as ethanol and nicotine, and provide new insights into the pathogenesis of RA. Paper I shows that a continuous intake of ethanol delays the onset and halts the progression of CIA in mice. This anti-arthritic effect is mediated by increased testosterone secretion leading to (i) decreased activation of transcription factor NF-κB, (ii) down-regulation of pro-inflammatory cyto- and chemokines and (iii) down-regulation of leukocyte migration into the joints. Paper II studies the effect of cigarette smoking and nicotine exposure in CIA mice. Results show that mice exposed to cigarette smoke develop a significantly milder arthritis with reduced destruction of joints. Nicotine-exposed mice show a tendency to decreased inflammation. Notably, exposure to cigarette smoke reduces antigen response and decreases the level of CII-specific antibodies. Paper III handles intervention with ethanol-sensitive glutamate receptors. CIA mice subjected to the NMDA receptor antagonist memantine show significantly decreased severity of arthritis and reduced destructive disease. We show that memantine up-regulates transcription factor Foxp3 and enhances formation of CD4+CD25+Foxp3+ regulatory T cells, which may be a potential reason for the anti-arthritic properties of the NMDA receptor blockade. In conclusion, our results provide new insights into the anti-inflammatory properties of environmental toxins such as ethanol and nicotine, as well as of blockade of the ethanol-sensitive NMDA receptor. Our findings from experimental studies need further validation in the population of RA patients.