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Review
. 2022 Jan:208:102172.
doi: 10.1016/j.pneurobio.2021.102172. Epub 2021 Sep 4.

Neuroimmune interactions and immunoengineering strategies in peripheral nerve repair

Kathryn L Wofford  1 , Robert B Shultz  2 , Justin C Burrell  3 , D Kacy Cullen  4
Affiliations
Review

Neuroimmune interactions and immunoengineering strategies in peripheral nerve repair

Kathryn L Wofford et al. Prog Neurobiol. 2022 Jan.

Abstract

Peripheral nerve injuries result in disrupted cellular communication between the central nervous system and somatic distal end targets. The peripheral nervous system is capable of independent and extensive regeneration; however, meaningful target muscle reinnervation and functional recovery remain limited and may result in chronic neuropathic pain and diminished quality of life. Macrophages, the primary innate immune cells of the body, are critical contributors to regeneration of the injured peripheral nervous system. However, in some clinical scenarios, macrophages may fail to provide adequate support with optimal timing, duration, and location. Here, we review the history of immunosuppressive and immunomodulatory strategies to treat nerve injuries. Thereafter, we enumerate the ways in which macrophages contribute to successful nerve regeneration. We argue that implementing macrophage-based immunomodulatory therapies is a promising treatment strategy for nerve injuries across a wide range of clinical presentations.

Keywords: Immunoengineering; Immunomodulation; Macrophages; Peripheral nerve injury; Regeneration.

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Conflict of interest statement

CONFLICT OF INTEREST

DKC is a co-founder and RBS is an employee of Axonova Medical, LLC, which is a University of Pennsylvania spin-out company focused on translation of advanced regenerative therapies to treat nervous system disorders. KLW has filed a patent application related to control of macrophage phenotype via intracellular microparticles (U.S. Patent App. PCT/US18/34906). No other author has declared a potential conflict of interest.

Figures

Figure 1.
Figure 1.. Macrophages contribute to peripheral nerve regeneration.
(A) Macrophages at the dorsal root ganglia release neurotrophic factors such as leukemia inhibitor factor (LIF) that stimulate axonal outgrowth. (B) Macrophages at the distal end target contribute to synapse formation and neurotransmitter regulation. (C-H) Macrophages at the injury site (C) clear myelin fragments and cellular debris, (D) regulate extracellular matrix (ECM) organization through secreting tissue inhibitors of metalloproteinase (TIMPs), (E) stimulate angiogenesis through secretion of vascular endothelial growth factor (VEGF), (F) recruit Schwann cells with chemokine ligand 3 (CCL3), (G) induce Schwann cell maturation through growth arrest specific 6 (GAS6), and (H) prevent ectopic growth with slit homolog 3 protein (Slit3) expression.
See this image and copyright information in PMC

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