New immune regulators of sciatic nerve regeneration? Lessons from the neighborhood

André L.Bombeiro ,Rodrigo G.Q.Fernandes,Julie C.Ribot

For decades,the immune system has been associated with host protection against infectious pathogens or tumors,while also contributing to autoimmunity.Notwithstanding,this paradigm is now changing,with recent studies highlighting novel roles for immune mediators in the maintenance of steady-state tissue homeostasis.In this perspective,we review some of the latest findings featuring immune modulators of the nervous system pathophysiology,with a special focus on interleukin (IL)-17.

IL-17 is a family of six different cytokines,of which IL-17A (henceforth IL-17) is the most studied and well-understood.Besides CD4+T helper 17 cells (Th17) and innate lymphoid cells (ILCs),IL-17 is secreted by unconventional T cells,namely natural killer T cells,mucosal associated invariant T cells,and γδ T cells.This cytokine is commonly referred as a pro-inflammatory mediator that binds to its surface heterodimer receptor (IL-17R),composed of the IL-17RA and IL-17RC subunits.IL-17 has been highly conserved across species,reflecting its critical role in counteracting infections at barrier sites and maintaining the homeostasis of mucosal tissues.Notwithstanding this,IL-17 triggers detrimental outcomes in the context of inflammation,namely in autoimmunity and cancer,which makes it a promising target for immunotherapy,as already proven for multiple sclerosis and psoriasis.

Likewise,IL-17 has been associated with the pathogenesis of neurodegenerative diseases,such as Parkinson’s disease,Alzheimer’s disease,and amyotrophic lateral sclerosis (Fu et al.,2022).On the other hand,recent evidence has pointed to an unexpected role for this cytokine in steadystate neurophysiology.For example,our group has pioneered the identification of a population of meningeal IL-17-producing γδ T cells (γδ17 T cells) in the lymphatics of the brain dura matter,from where they promoted hippocampal synaptic plasticity and short-term memory (Ribeiro et al.,2019).Others have shown that γδ17 T cells regulated anxiety by shaping the transcriptomic profile of prefrontal cortex glutamatergic neurons (Alves de Lima et al.,2020),as well as stress-induced social-avoidance behavior upon microbiome-driven activation and migration from the colon to the meninges,where they accumulated (Zhu et al.,2023).Interestingly,a similar gut-brain axis involving γδ17 T cells has been shown to trigger the onset of stroke,by amplifying the neuroinflammatory events that lead to the disruption of the blood-brain barrier (Benakis et al.,2016).By contrast,when produced by astrocytes in later stages of the disease,IL-17 induced neural precursor cell differentiation and subsequent functional recovery (Lin et al.,2016).

Altogether,these results highlight the complexity of IL-17 functions in the central nervous system (CNS) pathophysiology,which depends on the signaling timeframe,site of production,and cellular source.Adding another unexpected layer to this picture,IL-17 has been shown to play a dual role in a model of autism,depending on the ontogeny stage: in adult mice,lipopolysaccharide injection increased IL-17 production,which directly stimulated the cortical network to promote social behavior;while IL-17 signaling resulted in social impairment upon prenatal inflammation (Reed et al.,2020).

Besides the CNS,IL-17 also regulates the pathophysiology of the peripheral nervous system (PNS),where it has mostly been linked with chronic pain.In line with this,a recent study has shown that skin injury induced Th17 cells to produce IL-17 in the dermis,which promoted the regeneration of Trpv1+sensory neurons by enhancing their axonal growth (Enamorado et al.,2023).Consistently,RNA sequencing analysis of Th17 cells isolated from the injured skin revealed a transcriptomic signature typical of a tissue regeneration program,highlighting pathways associated with wound healing and nerve interaction (Enamorado et al.,2023).On the other hand,when exposed to IL-17,primary cultures of dorsal root ganglion sensory neurons upregulated the expression of genes implicated in neuronal regeneration and metabolism,among others (Enamorado et al.,2023).Likewise,upon skin injury,dorsal root ganglion neurons displayed a concomitant upregulation of the expression Il17ra and the activating transcription factor 3,which is known to promote axonal growth and functional recovery.Of note,the exposure to the skin commensalStaphylococcus aureuswas necessary for Th17 cell-specific expansion at the lesion site and subsequent nerve regeneration,while the control of bacterial burden was surprisingly independent of IL-17 (Enamorado et al.,2023).This adds to the growing body of knowledge regarding an intriguing immunemicrobiome interplay in tissue pathophysiology,with the microbiota inducing the production of IL-17,which in turn shapes the composition of the gut microbiota,namely upon neuro-inflammation (Papotto et al.,2021).

Other members of the IL-17 family have been involved in the homeostasis of the PNS.For instance,IL-17F (produced by γδ T cells) promoted the sympathetic innervation of the brown adipose tissue by stimulating adipocytesderived transforming growth factor-β production (Hu et al.,2020).Similarly,IL-17C (produced by keratinocytes) induced neurite growth and neuron survival,thus protecting the PNS upon herpes simplex virus infection (Peng et al.,2017).Together,these findings point at crucial pleiotropic functions of the IL-17 family in nerve biology and open many questions regarding the conservation of these processes and associated mechanisms in other scenarios,namely in the context of sciatica,a common neurological symptom that originates from an irritated,compressed,or inflamed sciatic nerve.Notably,and contrary to the CNS,the PNS is capable of regenerating after injury through a finely orchestrated process in which glial and immune cells actively participate.Immediately after damage to the sciatic nerve,a process known as Wallerian degeneration takes place,where axon segments disintegrate and the myelin breaks down.In this environment,damage-associated molecular patterns and other pro-inflammatory molecules,including tumor necrosis factor-α,IL-1β and CCL2,activate the initial immune response,which has mostly been attributed to macrophages (Zigmond and Echevarria,2019).One of the main functions of these cells is tissue debridement,allowing newly proliferating Schwann cells to align and form tubular structures inside of which extracellular matrix and neurotrophic growth factors are delivered.Those structures,supported by a macrophagedependent polarized vasculature,correctly guide the elongation of newly grown axons.In sum,nerve regeneration is viewed as a series of cellular and molecular events which progress from a proinflammatory,thus pro-degenerative,to a rather anti-inflammatory and pro-repair environment.This timeline has traditionally been associated with (and is thought to be respectively driven by) pro-inflammatory type 1 macrophages (M1-like) and anti-inflammatory type 2 macrophages (M2-like).Both subsets polarize in response to specific signals from the degenerative/regenerative milieu,resulting in their acquisition of a particular phenotype,metabolism,and functional properties (Zigmond and Echevarria,2019).However,it is worth noting that this M1/M2 dichotomy is overly simplistic,and in reality,the nerve is populated by a wide array of macrophages expressing a myriad of pro-and anti-inflammatory markers.

Other immune populations have been shown to ensure a successful Wallerian degeneration,typically by regulating the response mediated by macrophages.In fact,neutrophils are the first cell subset to infiltrate the injured nerve.They are critical for the recruitment of monocytes from peripheral circulation and their subsequent differentiation into macrophages.Serum components,such as complement proteins and antibodies also promote the recruitment of macrophages,as well as their opsonization of cellular and myelin debris,thus contributing to the clearance of tissue.On the other hand,the role of T cells has remained poorly explored,also mostly restricted to the type 1/type 2 dichotomy and linked to the response mediated by macrophages.During the initial stages of the degeneration process,CD4+type 1 helper T (Th1) cells contribute to the differentiation of M1 macrophages through the production of interferon-γ.In the second stage,Th2 cells support the polarization of M2 macrophages via the production of IL-4 and IL-13,thus stimulating axonal regeneration and remyelination (Zigmond and Echevarria,2019).

The exploration of the impact of other T cell subsets and their secreted mediators is a promising area of investigation that may pave the way to future therapeutic strategies for nerve repair.For example,regulatory T cells have been shown to infiltrate the injured sciatic nerve,where they proliferated and produced IL-10,which suppressed the Th1 response and decreased neuropathic pain (Davoli-Ferreira et al.,2020).Another recent study has identified a subset of CXCR5+CD8+T cells that impairs axonal regeneration after sciatic nerve injury,specifically in aged animals (Zhou et al.,2022).Interestingly,these cells were shown to be recruited by CXCL13,which could be pharmacologically antagonized to promote neurological recovery of the sensory function.

With this background in mind,and in view of IL-17 pleiotropic functions in neuropathophysiology,we suggest that this cytokine could be a key modulator of the regeneration of the injured sciatic nerve,potentially by regulating axonal growth (Figure 1).This hypothesis is supported by the analysis of publicly available datasets showing the upregulation of Il17ra by injured neurons in a model of sciatic nerve transection (Enamorado et al.,2023).Alternatively,IL-17 could orchestrate the myeloid cell response in the early stages or regulate Schwann cell-mediated myelination in the later stages of the sciatic nerve regenerative process.Besides being a promising target against chronic pain,we believe that the implication of the IL-17/IL-17R axis in peripheral neuropathies should be further explored.As in the CNS,this cytokine appears to have a dual role in the PNS where it can both promote tissue homeostasis and repair post-injury or potentiate chronic neuropathies by establishing a pro-inflammatory environment.

Figure 1｜A potential role of IL-17 in sciatic nerve regeneration.

Finally,we expect that advances from nextgeneration sequencing technologies will unveil novel immune candidates and associated molecular mechanisms,as recently illustrated by the analysis of a dataset decoding the transcriptional landscape of the dorsal root ganglion after sciatic nerve injury upon aging (Zhou et al.,2022).In a world where peripheral neuropathy is affecting more than 2% of the population and reaches up to 8% of the elderly,the understanding of the complete picture of the immune modulators in nerve regeneration will open key avenues for therapeutic interventions.

We thank the members of the Ribot Silva-Santos lab for thoughtful discussion.

This work was funded by the Fundacao para a Ciencia e Tecnologia (2020.00413.CEECIND and 2022.01244.PTDC,to JCR).

André L.Bombeiro*,Rodrigo G.Q.Fernandes,Julie C.Ribot*

Instituto de Medicina Molecular João Lobo

Antunes,Faculdade de Medicina,Universidade de Lisboa,Lisbon,Portugal

*Correspondence to:Julie C.Ribot,PhD,jribot@medicina.ulisboa.pt;André L.Bombeiro,PhD,andre.bombeiro@medicina.ulisboa.pt.https://orcid.org/0000-0002-7852-343X(Julie C.Ribot)

https://orcid.org/0000-0003-2303-8127 (André L.Bombeiro)

Date of submission:April 21,2023

Date of decision:June 25,2023

Date of acceptance:July 10,2023

Date of web publication:August 14,2023

https://doi.org/10.4103/1673-5374.382241

How to cite this article:Bombeiro AL,Fernandes RGQ,Ribot JC (2024) New immune regulators of sciatic nerve regeneration? Lessons from the neighborhood.Neural Regen Res 19(4):705-706.

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