TY - JOUR
T1 - IL-4 expressing cells are recruited to nerve after injury and promote regeneration
AU - Pan, Deng
AU - Schellhardt, Lauren
AU - Acevedo-Cintron, Jesús A.
AU - Hunter, Daniel
AU - Snyder-Warwick, Alison K.
AU - Mackinnon, Susan E.
AU - Wood, Matt
N1 - Funding Information:
M.D.W. has been the recipient of sponsored research agreements from Checkpoint Surgical, Inc. and has consulted for Renerva, LLC, AxoGen, Inc., Foundry Therapeutics, LLC, and The Foundry, LLC. No research agreements or consulting relationships affected the materials in this manuscript. No personal compensation was provided. None of the other authors have any conflicts of interest to disclosure.
Funding Information:
This work was supported in part by the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health (NIH) under award numbers R01 NS086773 (SEM), R01 NS115960 (MDW), and K08NS096232 (AKSW) to Washington University . The content is solely the responsibility of the authors and does not represent the views of the NIH or Washington University.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/1
Y1 - 2022/1
N2 - Interleukin-4 (IL-4) has garnered interest as a cytokine that mediates regeneration across multiple tissues including peripheral nerve. Within nerve, we previously showed endogenous IL-4 was critical to regeneration across nerve gaps. Here, we determined a generalizable role of IL-4 in nerve injury and regeneration. In wild-type (WT) mice receiving a sciatic nerve crush, IL-4 expressing cells preferentially accumulated within the injured nerve compared to affected sites proximal, such as dorsal root ganglia (DRGs), or distal muscle. Immunohistochemistry and flow cytometry confirmed that eosinophils (CD45+, CD11b+, CD64−, Siglec-F+) were sources of IL-4 expression. Examination of targets for IL-4 within nerve revealed macrophages, as well as subsets of neurons expressed IL-4R, while Schwann cells expressed limited IL-4R. Dorsal root ganglia cultures were exposed to IL-4 and demonstrated an increased proportion of neurons that extended axons compared to cultures without IL-4 (control), as well as longer myelinated axons compared to cultures without IL-4. The role of endogenous IL-4 during nerve injury and regeneration in vivo was assessed following a sciatic nerve crush using IL-4 knockout (KO) mice. Loss of IL-4 affected macrophage accumulation within injured nerve compared to WT mice, as well as shifted macrophage phenotype towards a CD206- phenotype with altered gene expression. Furthermore, this loss of IL-4 delayed initial axon regeneration from the injury crush site and subsequently delayed functional recovery and re-innervation of neuromuscular junctions compared to wild-type mice. Given the role of endogenous IL-4 in nerve regeneration, exogenous IL-4 was administered daily to WT mice following a nerve crush to examine regeneration. Daily IL-4 administration increased early axonal extension and CD206+ macrophage accumulation but did not alter functional recovery compared to untreated mice. Our data demonstrate IL-4 promotes nerve regeneration and recovery after injury.
AB - Interleukin-4 (IL-4) has garnered interest as a cytokine that mediates regeneration across multiple tissues including peripheral nerve. Within nerve, we previously showed endogenous IL-4 was critical to regeneration across nerve gaps. Here, we determined a generalizable role of IL-4 in nerve injury and regeneration. In wild-type (WT) mice receiving a sciatic nerve crush, IL-4 expressing cells preferentially accumulated within the injured nerve compared to affected sites proximal, such as dorsal root ganglia (DRGs), or distal muscle. Immunohistochemistry and flow cytometry confirmed that eosinophils (CD45+, CD11b+, CD64−, Siglec-F+) were sources of IL-4 expression. Examination of targets for IL-4 within nerve revealed macrophages, as well as subsets of neurons expressed IL-4R, while Schwann cells expressed limited IL-4R. Dorsal root ganglia cultures were exposed to IL-4 and demonstrated an increased proportion of neurons that extended axons compared to cultures without IL-4 (control), as well as longer myelinated axons compared to cultures without IL-4. The role of endogenous IL-4 during nerve injury and regeneration in vivo was assessed following a sciatic nerve crush using IL-4 knockout (KO) mice. Loss of IL-4 affected macrophage accumulation within injured nerve compared to WT mice, as well as shifted macrophage phenotype towards a CD206- phenotype with altered gene expression. Furthermore, this loss of IL-4 delayed initial axon regeneration from the injury crush site and subsequently delayed functional recovery and re-innervation of neuromuscular junctions compared to wild-type mice. Given the role of endogenous IL-4 in nerve regeneration, exogenous IL-4 was administered daily to WT mice following a nerve crush to examine regeneration. Daily IL-4 administration increased early axonal extension and CD206+ macrophage accumulation but did not alter functional recovery compared to untreated mice. Our data demonstrate IL-4 promotes nerve regeneration and recovery after injury.
KW - Functional recovery
KW - IL-4
KW - Interleukin
KW - Macrophage
KW - Nerve crush
KW - Nerve regeneration
KW - Peripheral nerve
UR - http://www.scopus.com/inward/record.url?scp=85118345635&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2021.113909
DO - 10.1016/j.expneurol.2021.113909
M3 - Article
C2 - 34717939
AN - SCOPUS:85118345635
VL - 347
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
M1 - 113909
ER -