CSF1R Stimulation Promotes Increased Neuroprotection by CD11c+ Microglia in EAE

Agnieszka Wlodarczyk,Anouk Benmamar-Badel,Oriane Cédile,Trevor Owens,Kirstine Nolling Jensen,Isabella Kramer,Nick Boe Elsborg

doi:10.3389/fncel.2018.00523

Agnieszka Wlodarczyk, Anouk Benmamar-Badel + Show 5 more

Open Access

https://doi.org/10.3389/fncel.2018.00523

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Abstract

Microglia are resident immune cells of the central nervous system. Their development and maintenance depend on stimulation of Colony Stimulating Factor-1 receptor (CSF1R). Microglia play an important role in neurodevelopment and a population of microglia that expresses the complement receptor CD11c is critical for primary myelination. This population is virtually absent in the healthy adult brain but increases dramatically upon neuroinflammatory conditions, and these microglia are suggested to play a protective role in central nervous system (CNS) diseases. To date, the molecular trigger for their expansion is unknown. Here we showed that stimulation of CSF1R by either of its ligands, CSF1 and interleukin (IL)-34, can induce expansion of CD11c+ microglia. In addition, such stimulation resulted in amelioration of EAE symptoms and decreased demyelination. Treatment with CSF1R ligands also induced expression of the chemokine CCL2, and we showed that experimental overexpression of CCL2 in the brain led to a dramatic increase 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 microglia biology and open new perspectives for modulating microglial activity in neuroinflammatory diseases such as multiple sclerosis.

Highlights

Microglia are resident macrophages of the central nervous system (CNS) that primarily mediate surveillance and immunological functions (Nimmerjahn et al, 2005; Kettenmann et al, 2011)
Since Colony Stimulating Factor-1 receptor (CSF1R) signaling is a potent inducer of microglial proliferation, differentiation and maintenance, we asked whether it could play a role in the generation of CD11c+ microglia
We observed an increase in CCL2 expression after 3 consecutive injections of both IL-34 and CSF1 that seemed proportional to observed CD11c+ microglial numbers, this did not reach statistical significance (Figure 1F)

Summary

Introduction

Microglia are resident macrophages of the central nervous system (CNS) that primarily mediate surveillance and immunological functions (Nimmerjahn et al, 2005; Kettenmann et al, 2011). Activation of CSF1R by its ligands, namely Colony Stimulating Factor-1 (CSF-1) and Interleukin (IL)-34, contributes to microglial proliferation and differentiation, and is critical for microglia development, since a dramatic reduction of microglial numbers is observed in mice lacking IL-34 (Wang et al, 2012). This lack of microglia in IL-34-KO mice leads to severe developmental abnormalities in the CNS (Elmore et al, 2014), underlining the importance of microglia for neurogenesis. Other recent studies point to microglia as key players in neurodevelopment

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