Csf1 Deficiency Dysregulates Glial Responses to Demyelination and Disturbs CNS White Matter Remyelination.

Bozena Kaminska,Jakub Mieczkowski,Bartosz Wylot,Sylwia Niedziolka,Malgorzata Zawadzka

doi:10.3390/cells9010099

Bozena Kaminska, Jakub Mieczkowski + Show 3 more

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https://doi.org/10.3390/cells9010099

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Abstract

Remyelination, a highly efficient central nervous system (CNS) regenerative process, is performed by oligodendrocyte progenitor cells (OPCs), which are recruited to the demyelination sites and differentiate into mature oligodendrocytes to form a new myelin sheath. Microglia, the specialized CNS-resident phagocytes, were shown to support remyelination through secretion of factors stimulating OPC recruitment and differentiation, and their pharmacological depletion impaired remyelination. Macrophage colony-stimulating factor (Csf1) has been implicated in the control of recruitment and polarization of microglia/macrophages in injury-induced CNS inflammation. However, it remains unclear how Csf1 regulates a glial inflammatory response to demyelination as well as axonal survival and new myelin formation. Here, we have investigated the effects of the inherent Csf1 deficiency in a murine model of remyelination. We showed that remyelination was severely impaired in Csf1-/- mutant mice despite the fact that reduction in monocyte/microglia accumulation affects neither the number of OPCs recruited to the demyelinating lesion nor their differentiation. We identified a specific inflammatory gene expression signature and found aberrant astrocyte activation in Csf1-/- mice. We conclude that Csf1-dependent microglia activity is essential for supporting the equilibrium between microglia and astrocyte pro-inflammatory vs. regenerative activation, demyelinated axons integration and, ultimately, reconstruction of damaged white matter.

Highlights

Inflammation, manifested by microglia/macrophage activation contributing to antigen presentation and secretion of pro-inflammatory cytokines and toxic factors, has been long considered as detrimental to injured white matter in demyelinating conditions, such as multiple sclerosis (MS) [1,2,3,4,5,6,7,8,9,10]
The colony stimulating factor 1 (Csf1)-/- mice represent a model of profound microglia deficiency in a spinal cord white matter and as such are useful to investigate the role of microglia depletion and
The Csf1-/- mice represent a model of profound microglia deficiency in a spinal cord white matter and as such are useful to investigate the role of microglia depletion and Csf1-Csf1R signalling-mediated mechanism in the inflammatory phase of remyelination

Summary

Introduction

Inflammation, manifested by microglia/macrophage activation contributing to antigen presentation and secretion of pro-inflammatory cytokines and toxic factors, has been long considered as detrimental to injured white matter in demyelinating conditions, such as multiple sclerosis (MS) [1,2,3,4,5,6,7,8,9,10]. Post-mortem evidence [1,11,12,13] as well as experimental data [14,15,16,17,18] showed that remyelination occurs most efficiently in early active lesions characterized by the extensive activity of inflammatory cells. It is well documented that endogenous myelin repair fails when the inflammatory response is experimentally reduced [20,21,22]. Both, activated microglia present in the CNS and macrophages derived from blood monocytes, contribute beneficially to remyelination as a source of growth factors during the early phases of regeneration, facilitating OPC

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