IL-6 trans-signalling is elevated in ALS models and drives TDP-43 induced inflammatory responses in microglia

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by chronic inflammation in both the central nervous system (CNS) and peripheral tissues. Interleukin-6 (IL-6) has been implicated in ALS pathology; however, IL-6 exhibits both anti-inflammatory and pro-inflammatory functions. Notably, IL-6 trans-signalling possesses pro-inflammatory properties and is emerging as a key contributor to neuroinflammation during neurodegeneration. In this study, we aimed to characterize the expression of the IL-6 trans-signalling pathway in ALS mouse models and investigate its role in ALS protein aggregate-mediated inflammation in microglia and peripheral immune cells. Our results revealed that the protein expression level of a key IL-6 trans-signalling component, soluble IL-6 receptor (sIL-6R), was significantly increased in the spinal cord and tibialis anterior (TA) muscles of both SOD1^G93A and rNLS8 TDP-43 transgenic mice. Additionally, using mouse primary microglia, human monocyte-derived microglia-like cells (MDMi), and blood peripheral immune cells, we demonstrated that recombinant TDP-43 protein elicits robust pro-inflammatory cytokine responses, including IL-6, TNF-α, IL-23, and MCP-1. These responses were attenuated when treated with a specific IL-6 trans-signalling inhibitor, sgp130Fc. Our findings suggest that the TDP-43-induced inflammatory response is, in part, IL-6 trans-signalling-dependent and highlight the role of IL-6 trans-signalling as a potential driver of chronic inflammation contributing to ALS pathology. These results support IL-6 trans-signalling as a promising therapeutic target for mitigating inflammation and slowing disease progression. Future research should explore the broader implications of modulating IL-6 trans-signalling in ALS.