Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis

Andrés Cruz-Herranz,Ryan D Schubert,Christian Cordano,Ester Cantó,Jung H Sin,Nicholas Baker,Frederike C Oertel,Ari J Green,Lakshmisahithi Rani,Michael Devereux,Garrett Timmons,Kicheol Kim,Sergio E Baranzini,Brady Michel

doi:10.1172/jci.insight.149228

Abstract

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1GFP/+–knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified — growth arrest–specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) — might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury.

Highlights

Microglia are the resident immune cells of the CNS and are part of the innate immune system [1]
Despite microglia being the most motile retinal innate immune cells, their activation in the retina has been only partially described in experimental autoimmune encephalitis (EAE); the number of resident microglia increases early [8]
Both microglia and infiltrating innate immune cells play a role in disease processes, and they likely participate in injury as well as protection [2, 10, 35, 36]

Summary

Introduction

Microglia are the resident immune cells of the CNS and are part of the innate immune system [1]. These cells produce inflammatory cytokines, proteases, and free radicals, which all contribute to CNS damage. [1] microglia maintain CNS integrity by removing apoptotic cells, providing trophic support, and potentially enhancing remyelination [2]. The heterogeneity of microglial phenotypes at different time points and in different CNS regions further diversify their roles [5, 6]. Animal studies that model human MS pathology are warranted to investigate the association of microglial activation with damage and to explore microglial phenotypes in distinct disease stages. Enriched pathways for ≥ 2-fold enhanced expression at 6 dpi versus baseline

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