Dynamic response of microglia/macrophage polarization following demyelination in mice

Abstract

Background The glial response in multiple sclerosis (MS), especially for recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), predicts the success of remyelination of MS plaques and return of function. As a central player in neuroinflammation, activation and polarization of microglia/macrophages (M/M) that modulate the inflammatory niche and cytokine components in demyelination lesions may impact the OPC response and progression of demyelination and remyelination. However, the dynamic behaviors of M/M and OPCs during demyelination and spontaneous remyelination are poorly understood, and the complex role of neuroinflammation in the demyelination-remyelination process is not well known. In this study, we utilized two focal demyelination models with different dynamic patterns of M/M to investigate the correlation between M/M polarization and the demyelination-remyelination process. Methods The temporal and spatial features of M/M activation/polarization and OPC response in two focal demyelination models induced by lysolecithin (LPC) and lipopolysaccharide (LPS) were examined in mice. Detailed discrimination of morphology, sensorimotor function, diffusion tensor imaging (DTI), inflammation-relevant cytokines, and glial responses between these two models were analyzed at different phases. Results The results show that LPC and LPS induced distinctive temporal and spatial lesion patterns. LPS produced diffuse demyelination lesions, with a delayed peak of demyelination and functional decline compared to LPC. Oligodendrocytes, astrocytes, and M/M were scattered throughout the LPS-induced demyelination lesions but were distributed in a layer-like pattern throughout the LPC-induced lesion. The specific M/M polarization was tightly correlated to the lesion pattern associated with balance beam function. Conclusions This study elaborated on the spatial and temporal features of neuroinflammation mediators and glial response during the demyelination-remyelination processes in two focal demyelination models. Specific M/M polarization is highly correlated to the demyelination-remyelination process probably via modulations of the inflammatory niche, cytokine components, and OPC response. These findings not only provide a basis for understanding the complex and dynamic glial phenotypes and behaviors but also reveal potential targets to promote/inhibit certain M/M phenotypes at the appropriate time for efficient remyelination.

Myeloid‐derived suppressor cells support remyelination in a murine model of multiple sclerosis by promoting oligodendrocyte precursor cell survival, proliferation, and differentiation

“…As for MDSC‐induced immunosuppression (Apolloni et al, 2000; Moliné‐Velázquez et al, 2011), one plausible explanation for the absence of clear, effective remyelination in vivo is that OPCs may need to engage in direct cell‐to‐cell mediated interactions with MDSCs. In order to reduce the well‐known effect of microglia over remyelination we chose (a) the comparatively less‐immunogenic LPC as demyelinating agent (Chu et al, 2019), and (b) then 7 days to wait for microglia return to quiescence. However, we accept that the soluble factors released by microglia may exert a pro‐remyelinating role besides the MDSC‐derived ones.…”

Longitudinal Intravital Microscopy Reveals Axon Degeneration Concomitant With Inflammatory Cell Infiltration in an LPC Model of Demyelination

“…Demyelination has been associated with the activation of phagocytic inflammatory cells (Chu et al, 2019;McMurran et al, 2019). Whether these inflammatory cells contribute to the degenerative processes was investigated by the application of our demyelination model on Thy1-CFP//LysM-EGFP mice.…”

Pomegranate peel extract ameliorates the severity of experimental autoimmune encephalomyelitis via modulation of gut microbiota

“… 2 , 26 Microglia and macrophages are activated in MS and secrete pro-inflammatory cytokines. 27 In addition, activated microglia and macrophages interact with encephalitogenic T cells via intercellular contact and cytokine-mediated communication, exacerbating neuroinflammation in EAE. 28 Herein, we evidence that oral PPE daily can effectively reduce the clinical score, demyelination, and axonal damage in MOG 35-55 -induced EAE mice.…”