Where there's smoke, there's fire: insights from murine models on the effect of cigarette smoke in rheumatoid arthritis development

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation and damage, leading to disability and pain. The etiology of RA is undefined but considered multifactorial, as interactions between genetics and environmental factors lead to the generation of autoantibodies that target synovial joints. Smoking is a well-established and widely studied risk factor for RA development and is associated with a reduced response to treatments and poor clinical outcomes. Murine models of inflammatory arthritis have provided many insights into the pathogenesis of RA and have recently been used to explore the relationship between cigarette smoking and RA. In this review, we comprehensively appraise the current literature investigating cigarette smoke exposure in murine models of inflammatory arthritis, focused on RA. The current literature indicates that the influence of smoke exposure on molecular and disease outcomes depends on the timepoint of exposure and genetic background of the mice. Further, dose-dependent increases in disease manifestations reproduce human clinical data that the intensity of smoking is linked to disease but demosntrate that there may be a plateau effect. Finally, we consolidate mechanistic findings to describe a potential mechanism through which cigarette smoke exacerbates murine arthritis. Understanding how these factors, genetics, timing, and intensity of exposure modulate response to CS in inflammatory arthritis models may lead to better drug development and personalized treatment strategies, ultimately improving outcomes for RA patients with a smoking history.

Keywords: PTMs; cigarette smoke; collagen-induced arthritis; cs; rf; rheumatoid Factor; rheumatoid arthritis; risk factors ra.

Figure 1

Proposed mechanism of CS exacerbating experimental arthritis (1). the first contact of CS is with the lungs which enhances inflammation and influx of immune cells in the lung, namely neutrophils which undergo NETosis to increase citrullination in the lung (2). The chronic inflammation and destruction of the lung may serve as the site of break in self-tolerance and generation of auto-reactive B cells against citrullinated proteins (ACPA) (3). The PAHs from cigarette smoke that enter the circulation from the lung engage the aryl hydrocarbon receptor (AHR) on T cells to drive a Th17 profile. Th17 cells are increased along with Il17a expression in lymph nodes and spleen which may then migrate to the joint (4). PAH interaction with AHR also drives increase in miR-132 production by Th17 cells which is packaged and secreted as extracellular vesicles (5). In the circulation there is increased EVs containing miR-132 from Th17 cells, as well as ACPA and citrullinated proteins, nicotine and its derivative cotinine, and heavy metals (6). The miR-132 drives osteoclastogenesis which drives bone damage (7). Increased ACPA in circulation binding to antigen in circulation and in the joint further enhances inflammation, increasing recruitment of inflammatory cells to the joint, such as neutrophils (8). Neutrophils undergo NETosis in the joint further driving citrullination within the joint providing increased antigen enhancing this loop of inflammation that drives bone and cartilage degradation.