Abstract
BACKGROUND: The terminal pathway of the innate immune complement system is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Terminal complement activation leads to generation of C5a, which through its receptor, C5aR1, drives immune cell recruitment and activation. Importantly, genetic or pharmacological blockage of C5aR1 improves motor performance and reduces disease pathology in hSOD1(G93A) rodent models of ALS. In this study, we aimed to explore the potential mechanisms of C5aR1-mediated pathology in hSOD1(G93A) mice by examining their skeletal muscles. RESULTS: We found elevated levels of C1qB, C4, fB, C3, C5a, and C5aR1 in tibialis anterior muscles of hSOD1(G93A) mice, which increased with disease progression. Macrophage cell numbers also progressively increased in hSOD1(G93A) muscles in line with disease progression. Immuno-localisation demonstrated that C5aR1 was expressed predominantly on macrophages within hSOD1(G93A) skeletal muscles. Notably, hSOD1(G93A) × C5aR1(-/-) mice showed markedly decreased numbers of infiltrating macrophages, along with reduced neuromuscular denervation and improved grip strength in hind limb skeletal muscles, when compared to hSOD1(G93A) mice. CONCLUSION: These results indicate that terminal complement activation and C5a production occur in skeletal muscle tissue of hSOD1(G93A) mice, and that C5a-C5aR1 signalling contributes to the recruitment of macrophages that may accelerate muscle denervation in these ALS mice.