Glia have emerged as key contributors to pathological and chronic pain mechanisms. On activation, both astrocytes and microglia respond to and release a number of signalling molecules, which have protective and/or pathological functions. Here we review the current understanding of the contribution of glia to pathological pain and neuroprotection, and how the protective, anti-inflammatory actions of glia are being harnessed to develop new drug targets for neuropathic pain control. Given the prevalence of chronic pain and the partial efficacy of current drugs, which exclusively target neuronal mechanisms, new strategies to manipulate neuron–glia interactions in pain processing hold considerable promise.

/pdf/pathological-and-protective-roles-of-glia-in-chronic-pain-gyzxsyh44u.pdf

Pathological and protective roles of glia in chronic pain

Recent studies have shown that macrophages play an important part in both tumor initiation and various key steps in growth and metastasis. These cells show a remarkable degree of plasticity during tumor development with a "switch" in macrophage phenotypes occurring during the course of tumor progression. During chronic inflammation they appear to predispose a given tissue to tumor initiation by the release of factors that promote neoplastic transformation. Following this, their phenotype shifts more toward one that is immunosuppressive and supports tumor growth, angiogenesis, and metastasis. In this review, we discuss the evidence for this plasticity of macrophage functions, the specific signaling mechanisms that may be regulating it, and the new targets for anticancer therapies highlighted by these findings.

Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms

During the resolution phase of inflammation, apoptotic leukocytes are efferocytosed by macrophages in a nonphlogistic fashion that results in diminished responses to bacterial moieties and production of anti-inflammatory cytokines. Complement receptor 3 and pro-resolving lipid mediators promote the engulfment of apoptotic leukocytes by macrophages. Here, we present evidence for the emergence of pro-resolving, CD11b(low) macrophages in vivo during the resolution of murine peritonitis. These macrophages are distinct from the majority of peritoneal macrophages in terms of their functional protein expression profile, as well as pro-resolving properties, such as apoptotic leukocyte engulfment, indifference to TLR ligands, and emigration to lymphoid organs. Notably, we also found macrophages convert from the CD11b(high) to the CD11b(low) phenotype upon interaction with apoptotic cells ex vivo. In addition, we found that the pro-resolving lipid mediators resolvin E1 and D1, and the glucocorticoid dexamethasone regulated pro-resolving macrophage functions in vivo. This regulation culminated in a novel pro-resolving function, namely reducing the apoptotic leukocyte ingestion requirement for CD11b(low) macrophage generation. These new phenotype and molecular pathway markers define the new satiated macrophage. Thus, we suggest that satisfying efferocytosis generates CD11b(low) macrophages that are essential for complete nonphlogistic containment of inflammatory agents and the termination of acute inflammation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.201040801

Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids.

https://escholarship.org/content/qt0z68j1r7/qt0z68j1r7.pdf?t=ppflgv

Tissue-Resident Macrophages Are Locally Programmed for Silent Clearance of Apoptotic Cells

The human cathelicidin LL-37 has broad-spectrum antimicrobial activity. It also participates at the interface of innate and adaptive immunity by chemoattracting immune effector cells, modulating the production of a variety of inflammatory mediators by different cell types, and regulating the differentiation of monocytes into dendritic cells. In this study, we investigated the effects of LL-37 on the differentiation of human monocytes into anti-inflammatory macrophages (MΦ-2; driven by M-CSF) versus proinflammatory macrophages (MΦ-1; driven by GM-CSF) as well as on fully differentiated MΦ-1 and MΦ-2. Results revealed that monocytes cultured with M-CSF in the presence of LL-37 resulted in macrophages displaying a proinflammatory signature, namely, low expression of CD163 and little IL-10 and profound IL-12p40 production on LPS stimulation. The effects of LL-37 on M-CSF-driven macrophage differentiation were dose- and time-dependent with maximal effects observed at 10 μg/ml when the peptide was present from the start of the cultures. The peptide enhanced the GM-CSF–driven macrophage differentiation. Exposure of fully differentiated MΦ-2 to LL-37 for 6 d resulted in macrophages that produced less IL-10 and more IL-12p40 on LPS stimulation than control MΦ-2. In contrast, LL-37 had no effect on fully differentiated MΦ-1. Peptide mapping using a set of 16 overlapping 22-mer peptides covering the complete LL-37 sequence revealed that the C-terminal portion of LL-37 is responsible for directing macrophage differentiation. Our results furthermore indicate that the effects of LL-37 on macrophage differentiation required internalization of the peptide. Together, we conclude that LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

LL-37 Directs Macrophage Differentiation toward Macrophages with a Proinflammatory Signature

Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages.

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Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages.