Therapeutic neutralization of the Interleukin-17 pathway in ALS
Systemic and neural inflammation that occurs in ALS patients is typified by elevation of the inflammatory cytokine IL-17A in ALS patient plasma and cerebral spinal fluid. Th17 T cells, the major cell type that produce IL-17A, are elevated in ALS patient blood and this Th17 elevation correlates with a more rapid ALS disease progression. IL-17A induces neurotoxic neutrophils that are elevated in ALS patient blood and cerebral spinal fluid and higher neutrophil levels correlate with poorer ALS patient survival. Mice that model the C9ORF72 repeat expansion – the most common genetic cause of ALS - develop elevated levels of IL-17A in plasma, have elevated Th17 cells and neutrophils in the blood and experience neural inflammation. We demonstrated that neutralization of IL-17A with blocking antibodies administered outside the central nervous system of C9orf72 mutant mice reduced neutrophils in blood, reduced neural inflammation of the spinal cord, and improved motor function (Limone et al., 2024). We seek to evaluate whether therapeutic neutralization of IL-17A in ALS patients to halt systemic and neural inflammation, slow motor decline, extend lifespan and improve patient quality of life using FDA approved humanized IL-17A neutralizing antibodies that are routinely prescribed in the clinic to treat psoriasis.
A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72-deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72-mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72-deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72-deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72-deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD. The ALS-associated C9orf72 gene product opposes IL-17A–dependent inflammation in myeloid and lymphoid cells. Patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) often exhibit autoimmune inflammation before neurological symptoms. Although mutated C9ORF72 has been linked to ALS and FTD, its role in neuroinflammation is unclear. Limone et al. found that hematopoietic loss of C9orf72 expression drove excess IL-17A inflammation. Myeloid-specific loss of C9orf72 was sufficient to cause severe autoimmunity. C9orf72-deficient mice had more myeloid cells with higher surface expression of costimulatory molecule CD80, which was potentiated by IL-17A. Patients with C9ORF72-related ALS similarly showed CD80 enrichment in spinal cord microglia. IL-17A neutralizing antibody reduced neuroinflammation in C9orf72-deficient mice, supporting further investigation of IL-17A–based therapies for ALS- and FTD-associated neuroinflammation. —Molly Ogle
@article{scitm2024il17a,author={Limone, Francesco and Couto, Alexander and Wang, Jin-Yuan and Zhang, Yingying and McCourt, Blake and Huang, Cerianne and Minkin, Adina and Jani, Marghi and McNeer, Sarah and Keaney, James and Gillet, Gaëlle and Gonzalez, Rodrigo Lopez and Goodman, Wendy A. and Kadiu, Irena and Eggan, Kevin and Burberry, Aaron},title={Myeloid and lymphoid expression of <i>C9orf72</i> regulates IL-17A signaling in mice},journal={Science Translational Medicine},volume={16},number={732},pages={eadg7895},year={2024},doi={10.1126/scitranslmed.adg7895},url={https://www.science.org/doi/abs/10.1126/scitranslmed.adg7895},eprint={https://www.science.org/doi/pdf/10.1126/scitranslmed.adg7895},}
