CONSTITUTIVE CD206 EXPRESSION ON MICROGLIA COUNTERACTS NEUROINFLAMMATION

Microglia, the resident macrophages of the central nervous system (CNS), have been assigned both detrimental and beneficial roles in inflammatory conditions like multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). We previously found that microglia effectively target pathogenic T-cells during neuroinflammation via the mannose receptor CD206 and thus counteract neuroinflammation. However, little is known about the involvement of the receptor itself in mediating beneficial microglia functions. Employing single-cell RNA sequencing (scRNA-seq) of physically interacting cells (PIC-seq) we here study the functional role of CD206 to control neuroinflammation.
To identify consequences of CD206 protein expression and to therapeutically exploit beneficial microglia activities within the CNS we generated a mouse line constitutively expressing CD206 in CX3CR1-positive cells and induced an experimental autoimmune encephalomyelitis (EAE). We made use of the PIC-Seq algorithm in CD206 overexpressing mice to gain direct insights into disease-relevant immune pathways affected upon interaction of CD206-positive microglia.
PIC-Seq of C57BL/6J EAE mice identified Th1 like cells as favored interaction partners of microglia during neuroinflammation, while interaction induced downregulation of CD206. Of note, constitutive CD206 expression in microglia reshaped their transcriptomic profile towards an enhanced beneficial repertoire and shifted microglial cells into an anti-inflammatory phenotype.
Functionally, CD206-overexpressing microglia reduced secretion of pro-inflammatory cytokines by Th1 cells. Furthermore, upregulation of CD206 expression in microglia was sufficient to counteract EAE disease. In summary, these findings indicate that constitutive CD206 expression through microglia reshapes their beneficial repertoire to enable microglial cells to counteract neuroinflammation, resulting in reduced clinical disease severity.