Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice

Author:

Limone Francesco1234ORCID,Couto Alexander123,Wang Jin-Yuan123,Zhang Yingying123ORCID,McCourt Blake5ORCID,Huang Cerianne5,Minkin Adina5ORCID,Jani Marghi5,McNeer Sarah5ORCID,Keaney James6,Gillet Gaëlle6ORCID,Gonzalez Rodrigo Lopez7ORCID,Goodman Wendy A.5ORCID,Kadiu Irena6,Eggan Kevin123ORCID,Burberry Aaron1235ORCID

Affiliation:

1. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

3. Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.

4. Leiden University Medical Center, LUMC, 2333 ZA Leiden, Netherlands.

5. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.

6. Neuroinflammation Focus Area, UCB Biopharma SRL, Braine-l'Alleud 1420, Belgium.

7. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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