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Selective proliferative response of microglia to alternative polarization signals.

ABSTRACT: Microglia are resident myeloid cells of the central nervous system (CNS) that are maintained by self-renewal and actively participate in tissue homeostasis and immune defense. Under the influence of endogenous or pathological signals, microglia undertake biochemical transformations that are schematically classified as the pro-inflammatory M1 phenotype and the alternatively activated M2 state. Dysregulated proliferation of M1-activated microglia has detrimental effects, while an increased number of microglia with the alternative, pro-resolving phenotype might be beneficial in brain pathologies; however, the proliferative response of microglia to M2 signals is not yet known. We thus evaluated the ability of interleukin-4 (IL-4), a typical M2 and proliferative signal for peripheral macrophages, to induce microglia proliferation and compared it with other proliferative and M2 polarizing stimuli for macrophages, namely colony-stimulating factor-1 (CSF-1) and the estrogen hormone, 17?-estradiol (E2).Recombinant IL-4 was delivered to the brain of adult mice by intracerebroventricular (i.c.v.) injection; whole brain areas or ex vivo-sorted microglia were analyzed by real-time PCR for assessing the mRNA levels of genes related with cell proliferation (Ki67, CDK-1, and CcnB2) and M2 polarization (Arg1, Fizz1, Ym-1) or by FACS analyses of in vivo BrdU incorporation in microglia. Primary cultures of microglia and astrocytes were also tested for proliferative effects.Our results show that IL-4 only slightly modified the expression of cell cycle-related genes in some brain areas but not in microglia, where it strongly enhanced M2 gene expression; on the contrary, brain delivery of CSF-1 triggered proliferation as well as M2 polarization of microglia both in vivo and in vitro. Similar to IL-4, the systemic E2 administration failed to induce microglia proliferation while it increased M2 gene expression.Our data show that, in contrast to the wider responsiveness of peripheral macrophages, microglia proliferation is stimulated by selected M2 polarizing stimuli suggesting a role for the local microenvironment and developmental origin of tissue macrophages in regulating self-renewal following alternative activating stimuli.

SUBMITTER: Pepe G

PROVIDER: S-EPMC5715534 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Selective proliferative response of microglia to alternative polarization signals.

Pepe Giovanna G De Maglie Marcella M Minoli Lucia L Villa Alessandro A Maggi Adriana A Vegeto Elisabetta E

Journal of neuroinflammation 20171204 1

<h4>Background</h4>Microglia are resident myeloid cells of the central nervous system (CNS) that are maintained by self-renewal and actively participate in tissue homeostasis and immune defense. Under the influence of endogenous or pathological signals, microglia undertake biochemical transformations that are schematically classified as the pro-inflammatory M1 phenotype and the alternatively activated M2 state. Dysregulated proliferation of M1-activated microglia has detrimental effects, while a ...[more]

PMID: 29202771

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Project description: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.

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Selective proliferative response of microglia to alternative polarization signals.

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Selective proliferative response of microglia to alternative polarization signals.

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