Abstract
BackgroundThe 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 hSOD1G93A rodent models of ALS. In this study, we aimed to explore the potential mechanisms of C5aR1-mediated pathology in hSOD1G93A mice by examining their skeletal muscles.ResultsWe found elevated levels of C1qB, C4, fB, C3, C5a, and C5aR1 in tibialis anterior muscles of hSOD1G93A mice, which increased with disease progression. Macrophage cell numbers also progressively increased in hSOD1G93A muscles in line with disease progression. Immuno-localisation demonstrated that C5aR1 was expressed predominantly on macrophages within hSOD1G93A skeletal muscles. Notably, hSOD1G93A × 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 hSOD1G93A mice.ConclusionThese results indicate that terminal complement activation and C5a production occur in skeletal muscle tissue of hSOD1G93A mice, and that C5a-C5aR1 signalling contributes to the recruitment of macrophages that may accelerate muscle denervation in these ALS mice.
Highlights
The terminal pathway of the innate immune complement system is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS)
There is no comprehensive overview of which complement pathway is dysregulated in the skeletal muscle of hSOD1G93A mice during disease progression
The tibialis anterior (TA) muscle of hSOD1G93A mice was chosen for this study as it consists of fast-twitch muscle fibres that are preferentially affected in these animals when compared to slow-twitch muscle fibres [21, 22]
Summary
The terminal pathway of the innate immune complement system is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Numerous clinical and animal studies have demonstrated strong up-regulation of activation fragments of complement components C1q, C3, and C4 in the serum, cerebrospinal fluid and neurological tissue (including spinal cord and motor cortex) of ALS patients and animal models of ALS [7,8,9]. Despite this strong evidence of early complement factor upregulation in ALS, specific genetic deletion of C1q, C3, and
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