Abstract
Daily moderate exercise (DME) and stress management are underemphasized in the care of patients with lupus nephritis (LN) due to a poor comprehensive understanding of their potential roles in controlling the inflammatory response. To investigate these effects on murine LN, disease progression was monitored with either DME or social disruption stress (SDR) induction in NZM2410/J mice, which spontaneously develop severe, early-onset LN. SDR of previously established social hierarchies was performed daily for 6 days and DME consisted of treadmill walking (8.5 m/min for 45 min/day). SDR significantly enhanced kidney disease when compared to age-matched, randomly selected control counterparts, as measured by histopathological analysis of H&E staining and immunohistochemistry for complement component 3 (C3) and IgG complex deposition. Conversely, while 88% of non-exercised mice displayed significant renal damage by 43 weeks of age, this was reduced to 45% with exercise. DME also reduced histopathology in kidney tissue and significantly decreased deposits of C3 and IgG complexes. Further examination of renal infiltrates revealed a macrophage-mediated inflammatory response that was significantly induced with SDR and suppressed with DME, which also correlated with expression of inflammatory mediators. Specifically, SDR induced IL-6, TNF-α, IL-1β, and MCP-1, while DME suppressed IL-6, TNF-α, IL-10, CXCL1, and anti-dsDNA autoantibodies. These data demonstrate that psychological stressors and DME have significant, but opposing effects on the chronic inflammation associated with LN; thus identifying and characterizing stress reduction and a daily regimen of physical activity as potential adjunct therapies to complement pharmacological intervention in the management of autoimmune disorders, including LN.
Highlights
Lupus nephritis (LN), a debilitating clinical manifestation of systemic lupus erythematous (SLE) contributing to disease morbidity, affects more than 50% of adult and pediatric patients with lupus (Imran et al, 2015)
Stress reduction programs offered to patients with SLE have demonstrated improved disease activity (Williams et al, 2014) and literature shows the positive effects of exercise in improvement of SLE disease management and clinical outcome (Ayán and Martín, 2007)
Our data characterize the effects of SDR and daily moderate exercise (DME) on murine LN in the NZM2410/J model and demonstrate that SDR significantly exacerbates the inflammatory process whereas this response is dramatically reduced with DME
Summary
Lupus nephritis (LN), a debilitating clinical manifestation of systemic lupus erythematous (SLE) contributing to disease morbidity, affects more than 50% of adult and pediatric patients with lupus (Imran et al, 2015). The precise effects of psychological stress modification and exercise in autoimmunemediated inflammatory disease, including LN, remain relatively unknown. Our previous research has shown that psychological stressors and moderate exercise elicit opposing immunomodulatory effects. We have shown that daily moderate exercise (DME) can significantly reduce systemic inflammatory responses following lipopolysaccharide injection in mice by suppressing NF-κB activity (manuscript in review). These effects were transient and lost after 24 h, which suggests greater efficacy with a daily regimen. The influence of psychological stressors or daily moderate exercise on LNassociated inflammatory processes and disease pathology has yet to be comprehensively examined
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