C9orf72 in myeloid cells suppresses STING-induced inflammation

Area of Science:

• Neuroimmunology
• Genetics of Neurodegeneration
• Innate Immunity

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share genetic origins, with C9orf72 repeat expansions being the most common cause of familial forms (C9-ALS/FTD).
• Autoimmune disorders are frequently observed in ALS and FTD patients, but the underlying mechanisms remain unclear.
• Reduced C9orf72 protein levels in C9-ALS/FTD are linked to RNA and dipeptide accumulation.

Purpose of the Study:

• To investigate the role of C9orf72 in myeloid cells concerning immune dysregulation in C9-ALS/FTD.
• To explore the involvement of the STING-interferon pathway in the pathogenesis of C9-ALS/FTD.
• To identify potential therapeutic targets for C9-ALS/FTD.

Main Methods:

• Utilized C9orf72 knockout mouse models (C9orf72-/-) and mice with partial C9orf72 deficiency.
• Analyzed immune cell activation, particularly dendritic cells and myeloid cells, focusing on type I interferon responses.
• Investigated the STING (stimulator of interferon genes) pathway, including STING degradation and its role in inflammation.
• Examined patient-derived samples (macrophages, blood, brain tissue) from C9-ALS/FTD and sporadic ALS/FTD individuals.
• Tested the efficacy of STING inhibitors in preclinical models and patient-derived cells.

Main Results:

• Loss of C9orf72 in myeloid cells alone recapitulated inflammatory phenotypes observed in complete knockout mice.
• C9orf72-/- myeloid cells exhibited heightened type I interferon responses, particularly hyperresponsiveness to STING activators.
• Impaired autolysosomal degradation of STING was identified in C9orf72-/- myeloid cells.
• Blocking STING reduced inflammation and splenomegaly in C9orf72-/- mice and suppressed elevated type I interferon signatures in C9-ALS/FTD patient samples.
• Mice with C9orf72 deficiency showed increased susceptibility to experimental autoimmune encephalitis.

Conclusions:

• Reduced C9orf72 levels in C9-ALS/FTD patients lead to an altered immunophenotype characterized by STING-mediated type I interferon induction and inflammation.
• The STING-interferon pathway is a critical driver of neuroinflammation in C9-ALS/FTD.
• Targeting the STING pathway with inhibitors presents a promising therapeutic strategy for C9-ALS/FTD.