Role of macrophages in peripheral nerve injury and repair

Abstract

Resident and inflammatory macrophages are essential effectors of the innate immune system. These cells provide innate immune defenses and regulate tissue and organ homeostasis. In addition to their roles in diseases such as cancer, obesity and osteoarthritis, they play vital roles in tissue repair and disease rehabilitation. Macrophages and other inflammatory cells are recruited to tissue injury sites where they promote changes in the microenvironment. Among the inflammatory cell types, only macrophages have both pro-inflammatory (M1) and anti-inflammatory (M2) actions, and M2 macrophages have four subtypes. The co-action of M1 and M2 subtypes can create a favorable microenvironment, releasing cytokines for damaged tissue repair. In this review, we discuss the activation of macrophages and their roles in severe peripheral nerve injury. We also describe the therapeutic potential of macrophages in nerve tissue engineering treatment and highlight approaches for enhancing M2 cell-mediated nerve repair and regeneration.

Keywords: function; macrophage; nerve injury; nerve regeneration; nerve repair; neural regeneration; origin; polarization; tissue engineering.

Figure 1

Under the regulation of cytokines (multi-CSF and GM-SCF), bone marrow-derived macrophages differentiate into mononuclear cells, and then gradually become mature macrophages that can be released into the circulation. IFN-γ, TNFα and LPS stimulate macrophages into M1, IL-4 and IL-13 into M2a, IC and TLR into M2b, and IL-10 into M2c; A_2AR agonist stimulates them into M2d. M1 macrophages induce a pro-inflammatory response, whereas M2 macrophages induce an anti-inflammatory response, and both exist in dynamic equilibrium (Chen et al., 2015). Multi-CSF: Multi-colony stimulating factor; GM-CSF: granulocyte macrophage colony stimulating factor; IFN-γ: interferon gamma; TNFα: tumor necrosis factor alpha; LPS: lipopolysaccharides; IC: immune complexes; TLR: toll-like receptor; A2AR: adenosine A2A receptor; IL: interleukin; IL-1R: IL-1 receptor. Adapted from Chen et al. (2015) and Helft et al. (2015).

Figure 2

Injury alters the peripheral nerve microenvironment. Peripheral nerve damage promotes Wallerian degeneration, axonal degeneration, BNB compromise, myelin breakdown and macrophage infiltration. In Wallerian degeneration, Schwann cells undergo dedifferentiation, and along with macrophages, participate in the clearance of debris. Macrophages promote Wallerian degeneration, detect ischemia and promote angiogenesis by releasing VEGF and VEGF-1, all of which serve to promote the migration and proliferation of Schwann cells by releasing IL-10, TGF-β, NGF and BDNF, and working as a scavenger, while maintaining an M1/M2 dynamic balance. In neural tissue engineering, the adsorption of cytokines on the nerve scaffold (e.g., IL-10, IL-4, IFN-γ) increases the ratio of M2 macrophages, thereby promoting nerve regeneration. VEGF: Vascular endothelial growth factor; TGF-β: transforming growth factor-β; NGF: nerve growth factor; BDNF: brain-derived neurotrophic factor; IL: interleukin; IFN-γ: interferon-γ; BNB: blood-nerve barrier. Adapted from Cattin et al. (2015) and Chen et al. (2015).