Although a definitive link between neuroinflammation and human IS requires further study, inflammatory origins of scoliosis are not inconsistent with human clinical and genetic studies. Hyper-IgE (immunoglobulin E) syndrome, characterized by frequent bacterial infection and inflammation, has been associated with developmental scoliosis (
31). Similarly, more than 50% of patients characterized by recurring nontuberculosis mycobacterial infection present with idiopathic-like spinal curvatures (
32). To date, the biological consequences of most IS-associated variants identified in genetic and genome-wide association studies remain uncertain (
1). For example, IS-associated variants linked to GPR126 have been functionally interrogated largely in the context of musculoskeletal origins of scoliosis (
4,
33). However, because myelination requires GPR126 (
34), regional demyelinating events downstream of GPR126 dysfunction could activate microglial inflammatory signals that initiate IS-like spinal curvature. Novel neuroinflammatory origins of IS identified in this study thus warrant a reexamination and interpretation of human IS clinical and genetic data.
Strikingly, we have demonstrated that treatment with common NSAIDs can have a significant and positive impact on the incidence and severity of scoliosis in our ptk7 mutant models. Notably, prophylactic treatment with NAC reduced the incidence of scoliosis in experimental cohorts by 79%. Furthermore, administration of NAC after scoliosis onset significantly reduced the severity of spinal curve progression. NAC is considered a well-tolerated and safe medication, with emerging clinical use for treating neurological and neurodevelopmental disorders in both children and adults [reviewed in (
23,
35)]. The therapeutic potential of NAC in treating IS remains to be determined. However, given that simple immunomodulating therapies prove effective in managing zebrafish idiopathic-like spinal deformities, conservation of the mechanism could have profound impacts on the future prevention and treatment of human scoliosis.