Immune Response in the Skeletal Muscles is Pivotal to Counteract ALS

Growing evidence suggests a prominent role of the immune system in ALS pathoprogression, the most common and fatal adult-onset neuromuscular disorder

We previously reported that MCP1/CCL2, one of the most potent pro-inflammatory chemokines, is strongly upregulated in the nervous system of C57 slow-progressing than 129Sv fast-progressing SOD1G93A mice, the latter showing a poor immune response and an accelerated peripheral nerve and muscle degeneration. 

Given the pivotal role of MCP1-mediated signalling in driving damaged axons and muscle regeneration, we boosted the chemokine along the motor unit of the SOD1G93A models through a single intramuscular injection of a self-complementary adeno-associated virus serotype 9 vector engineered with the Mcp1 gene. 

Our observations revealed that SOD1G93A mice responded positively to MCP1 boosting, anticipating the recruitment and phenotypic switch of leucocytes from the pro- to the anti-inflammatory fingerprint within the peripheral compartment. This sustained the activation of the myogenic programme and nerve regeneration, finally slackening off the motor symptoms progression. 

Immune-mediated muscle regeneration is a high flexible process, targetable at different levels. While MCP1 muscle-boosting forced macrophage recruitment into skeletal muscle, it has no direct effect in eliciting their shift from a pro to anti-inflammatory profile. This process occurred spontaneously during early disease stages in SOD1G93A mice but was exhausted as the disease progressed. Accordingly, we evaluated the possibility of sustaining macrophage transition exogenously to trigger muscle stem cell (satellite cells; SCs) conversion to mature myofibres. We found that SOD1G93A mice intramuscularly challenged with IL-10 showed macrophage polarisation towards an anti-inflammatory and pro-regenerative phenotype, and reduced hindlimb muscle wasting due to an increased satellite cell differentiation established in ex-vivo isolated transgenic SCs. 

We provided direct evidence underlying the pivotal role of the innate immune system in driving skeletal muscle regeneration, spotlighting that boosting a peripheral immune response is required to mitigate the pathological process in ALS. 

Intriguingly, our data showed a novel immune-unrelated role of MCP1 in promoting motor axon regeneration and modulating neuroinflammation in the nervous system of SOD1G93A mice, with the overall effect of reducing neurodegeneration. 

Altogether, these observations highlight the immune response as a critical determinant for disease variability and provide a reasonable explanation for the failure of systemic immunomodulatory treatments suggesting new potential strategies to hamper ALS progression.