IFN-Induced Protein with Tetratricopeptide Repeats 2 Limits Autoimmune Inflammation by Regulating Myeloid Cell Activation and Metabolic Activity

Author:

Kim Dongkyun1ORCID,Rai Nagendra Kumar2ORCID,Burrows Amy3ORCID,Kim Sohee1,Tripathi Ajai2ORCID,Weinberg Samuel E.4ORCID,Dutta Ranjan2ORCID,Sen Ganes C.3,Min Booki1ORCID

Affiliation:

1. *Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL;

2. †Department of Neuroscience, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH;

3. ‡Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH; and

4. §Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL

Abstract

Abstract Besides antiviral functions, type I IFN expresses potent anti-inflammatory properties and is being widely used to treat certain autoimmune conditions, such as multiple sclerosis. In a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, administration of IFN-β effectively attenuates the disease development. However, the precise mechanisms underlying IFN-β–mediated treatment remain elusive. In this study, we report that IFN-induced protein with tetratricopeptide repeats 2 (Ifit2), a type I and type III IFN-stimulated gene, plays a previously unrecognized immune-regulatory role during autoimmune neuroinflammation. Mice deficient in Ifit2 displayed greater susceptibility to experimental autoimmune encephalomyelitis and escalated immune cell infiltration in the CNS. Ifit2 deficiency was also associated with microglial activation and increased myeloid cell infiltration. We also observed that myelin debris clearance and the subsequent remyelination were substantially impaired in Ifit2−/− CNS tissues. Clearing myelin debris is an important function of the reparative-type myeloid cell subset to promote remyelination. Indeed, we observed that bone marrow–derived macrophages, CNS-infiltrating myeloid cells, and microglia from Ifit2−/− mice express cytokine and metabolic genes associated with proinflammatory-type myeloid cell subsets. Taken together, our findings uncover a novel regulatory function of Ifit2 in autoimmune inflammation in part by modulating myeloid cell function and metabolic activity.

Funder

HHS | National Institutes of Health

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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