In this study, the authors show that oligodendrocyte differentiation and remyelination after a CNS lesion coincides with a switch in microglial/macrophage polarization from a pro-inflammatory, M1, phenotype to an anti-inflammatory, M2, phenotype. This M2-dependant effect was in part mediated by secretion of the TGFβ family member, Activin-A.

M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination

Background: Although macrophages (MW) are known as essential players in wound healing, their contribution to recovery from spinal cord injury (SCI) is a subject of debate. The difficulties in distinguishing between different MW subpopulations at the lesion site have further contributed to the controversy and led to the common view of MW as functionally homogenous. Given the massive accumulation in the injured spinal cord of activated resident microglia, which are the native immune occupants of the central nervous system (CNS), the recruitment of additional infiltrating monocytes from the peripheral blood seems puzzling. A key question that remains is whether the infiltrating monocyte-derived MW contribute to repair, or represent an unavoidable detrimental response. The hypothesis of the current study is that a specific population of infiltrating monocyte-derived MW is functionally distinct from the inflammatory resident microglia and is essential for recovery from SCI. Methods and Findings: We inflicted SCI in adult mice, and tested the effect of infiltrating monocyte-derived MW on the recovery process. Adoptive transfer experiments and bone marrow chimeras were used to functionally distinguish between the resident microglia and the infiltrating monocyte-derived MW. We followed the infiltration of the monocyte-derived MW

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Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.

IL-21- and CD40-dependent cognate interactions with T cells are identified as key drivers for the generation of IL-10-producing regulatory B cells, which can protect against autoimmune disease Subsets of regulatory B cells have been identified in both mice and humans, including the regulatory B10 cell subset that produces the inhibitory cytokine interleukin-10 (IL-10) B-cell derived IL-10 can protect against autoimmune disease in mice Here, Thomas Tedder and colleagues identify IL-21- and CD-40-dependent cognate interactions with T cells as key drivers for the generation of IL-10-producing CD5+ regulatory B cells Transfer of in vitro-expanded regulatory B cells is shown to suppress signs of disease in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis This work suggests a novel strategy for the treatment of severe autoimmune diseases for which effective therapies are not available B cells regulate immune responses by producing antigen-specific antibodies1 However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells2,3,4 Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified2,3,4,5 Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice5,6,7 How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies

Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions

Multiple Sclerosis: Mechanisms and Immunotherapy

Increasing evidence has supported the important role of mesenchymal stem cells (MSCs) in wound healing, however, the underlying mechanism remains unclear. Recently, we have isolated a unique population of MSCs from human gingiva (GMSCs) with similar stem cell-like properties, immunosuppressive, and anti-inflammatory functions as human bone marrow-derived MSCs (BMSCs). We describe here the interplay between GMSCs and macrophages and the potential relevance in skin wound healing. When cocultured with GMSCs, macrophages acquired an anti-inflammatory M2 phenotype characterized by an increased expression of mannose receptor (MR; CD206) and secretory cytokines interleukin (IL)-10 and IL-6, a suppressed production of tumor necrosis factor (TNF)-α, and decreased ability to induce Th-17 cell expansion. In vivo, we demonstrated that systemically infused GMSCs could home to the wound site in a tight spatial interaction with host macrophages, promoted them toward M2 polarization, and significantly enhanced wound repair. Mechanistically, GMSC treatment mitigated local inflammation mediated by a suppressed infiltration of inflammatory cells and production of IL-6 and TNF-α, and an increased expression of IL-10. The GMSC-induced suppression of TNF-α secretion by macrophages appears to correlate with impaired activation of NFκB p50. These findings provide first evidence that GMSCs are capable to elicit M2 polarization of macrophages, which might contribute to a marked acceleration of wound healing.

/pdf/human-gingiva-derived-mesenchymal-stem-cells-elicit-46v84yjtjs.pdf

Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing.

Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of T(H)2 cells and CD4+CD25+FoxP3+ regulatory T cells (T(reg)) independent of antigen specificity. Type II monocyte-induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed T(H)17 cell development and promoted both T(H)2 differentiation and expansion of T(reg) cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity.

Cynthia D Rundle

Papers

Type II monocytes modulate T cell-mediated central nervous system autoimmune disease