023 – CSF1R stimulation promotes increased neuroprotection by CD11c+ microglia in EAE
Benmamar-Badel Anouk (1, 2) – Agnieszka Wlodarczyk (1) – Oriane Cdile (1) – Kirstine Nolling Jensen (1) – Isabella Kramer (1) – Nick Boe Elsborg (1) – Trevor Owens (1)
Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark (1) – Department of Neurology, Slagelse Hospital, Slagelse, Denmark (2)
Tissue-resident macrophages exert crucial functions in health and disease such as immune surveillance, orchestration of inflammatory activity and tissue repair. Their development and maintenance depend on colony stimulating factor 1 receptor (CSF1R) and its two ligands: CSF1 and IL-34. Microglia are the tissue-resident macrophages of the central nervous system (CNS). They originate from yolk sac progenitors early in life, and play an important role in neurodevelopment. We identified a population of microglia that expresses the complement receptor CD11c and is critical for primary myelination in neonatal CNS. This population is virtually absent in the healthy adult CNS but increases dramatically upon neuroinflammatory conditions, and CD11c+ microglia are suggested to play a CNS-protective role. To date, the molecular trigger for their expansion is unknown. Here we show that in vivo stimulation of CSF1R by either of its ligands can induce expansion of CD11c+ microglia. In addition, transfer of neonatal CD11c+ microglia or CSF1R stimulation resulted in amelioration of symptoms and decreased demyelination in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Treatment with CSF1R ligands also induced expression of the chemokine CCL2, and we showed that experimental overexpression of CCL2 in the brain led to expansion of CD11c+ microglia, independent of CCR2. Moreover, this led to elevated CSF1 expression, suggesting a positive feedback loop between CSF1R and CCL2. These data provide new insights to tissue-resident macrophage biology, through the example of microglia, and open new perspectives for modulating their activity in inflammatory diseases.