When IL-17 gets on your nerves

Abstract

Microbiota-induced IL-17 production mediates central nervous system (CNS) processes and animal behavior. However, its role on the peripheral nervous system (PNS) remains largely unknown. Enamorado et al. demonstrate that commensal-specific Th17 cells are recalled following tissue injury to support local nerve regeneration, a process orchestrated by IL-17 signaling on peripheral neurons.

Barrier surfaces play host to a community of microorganisms that span microbial kingdoms, including bacteria and fungi. An appealing idea that has recently gained traction is that the immune and nervous systems work together to provide a head start on controlling new or spreading infections. In this issue of Cell, Enamorado et al. ¹ elegantly demonstrate that Staphylococcus aureus commensalism of the skin leads to such ‘preemptive immunity’, enhancing tissue integrity upon succeeding injury and/or infection. Unexpectedly, preemptive immunity is mediated not only through classic immune defense mechanisms but also through direct IL-17 receptor signaling on peripheral neurons.

IL-17(A)-producing cells include conventional (CD4⁺) Th cells and innate lymphocytes (γδ T, ILC3s), collectively termed “Type 17”. These cells produce their eponymous cytokine, as well as IL-17F, IL-22 and in some cases IL-10, GM-CSF or IFNγ. Type 17 immunity is central to maintaining appropriate balance between pathogenic insults, commensal microbes, and tissue-reparative processes. Initially described in 2005, Th17 cells represented the first major revision of the Th1/Th2 paradigm in two decades. Obscure at the time, IL-17-family ligands and their receptors were notable for their lack of homology to known immune cytokine subclasses. IL-17 emerged as essential for controlling mucocutaneous Candida albicans infections, since mice and humans with IL-17 signaling defects are exquisitely sensitive to candidiasis, especially its oral manifestation ².

Intriguing links between IL-17 and neurons have emerged from various avenues of investigation. Optogenetics approaches revealed that TRPV1⁺ peripheral nerve activation is sufficient to drive Type 17 responses, independent of infection or even tissue injury. Moreover, this neuroimmune axis prompts “anticipatory” immunity to adjacent regions through a shared neuronal network ³. In addition to impacting the PNS, IL-17 modulates central nervous system (CNS) function, shaping behavior (social communication, anxiety) and outcomes of brain injury ^4-6. A consortium of fungal species residing in the gut, including C. albicans, can also influence social behavior, mediated via IL-17R signaling on neurons ⁷.

The present study addresses important consequences of bacterial commensalism and Type 17 cell activation in promoting neuronal repair, modeled by intradermal infection with an isolate of Staphylococcus aureus (SA). Following SA colonization, RORγt⁺CD4⁺ Th17 cells accumulated in skin, yet unexpectedly mice did not demonstrate the expected tissue thickening, inflammation or augmented Th1 responses that would normally be characteristic of SA infection. Adoptive transfer of SA-specific T cells from a newly generated TCR transgenic strain showed that these differentiated Th17 cells depend on IL-1, microbial viability, and intact lymphoid structures. Nonetheless, Th17 cells induced by SA colonization provided neither local nor systemic protection against infection by the same strain, raising the possibility of an alternative function for these cells.

Indeed, SA-specific Th17 cells exhibited not only a prototypical IL-17 gene signature but were additionally enriched for genes related to neuronal response and function. Notably, SA colonization prompted accumulation of Th17 cells proximal to dermal neurons at the site of injury (Fig 1), leading to neuronal regeneration in an IL-17-dependent manner. The IL-17 receptor (Il17ra) was upregulated in damaged dorsal root ganglion (DRG) neurons, which innervate skin and transmit sensory information. Upon injury, cervical DRG2 neurons upregulated Activating Transcription Factor 3 (Atf3) whose expression correlated with Il17ra. The authors exploited this connection by using it to delete Il17ra selectively in damaged (i.e., Atf3⁺) neurons, resulting in a failure of SA colonization to facilitate nerve regeneration. Interestingly, while loss of Il17ra in Trpv1+ sensory neurons obliterated the protective effect of SA colonization on cell repair, the DRG response to mechanical stimulation was preserved, indicating selective functionality conferred by commensal colonization on sensory neurons.

Fig 1.

Commensal-specific Th17 cells support nerve regeneration during skin injury or infection through direct signaling to injured sensory neurons via IL-17RA. S. aureus (SA) topical colonization induces SA-specific Th17 cells that accumulate proximal to dermal neurons. Upon skin injury, cervical DRG2 neurons respond with upregulation of Atf3 and Il17ra. This process fosters neuronal regeneration in an IL-17-dependent manner (right panel) which does not occur in the absence of SA colonization (left panel).

Cumulatively, this elegant study emphasizes the capacity of Type 17 cells through their signature cytokine IL-17 to “pass the torch” to neurons, illustrating bidirectionality of Th17/ neuronal interactions triggered by skin colonizers¹⁰ and expanding upon other recently described mechanisms demonstrating how neuronal loss is mitigated even in the face of pathogen exposure⁸. These studies raise the question of how other Type 17 cytokines may contribute to this commensal-Type 17-neuron axis. For example, IL-22 is nonredundant in immunity to many mucosal infections, but the key cell targets are not necessarily shared. For example, in candidiasis, IL-17 and IL-22 act on distinct cell types within the stratified oral epithelium ⁹. With regards to the CNS, IL-22 is not found in circulation⁷, nor are its receptor subunits detectable by single cell RNASeq on CNS neurons, suggesting that IL-22 is unlikely to affect neurons directly. However, ILC3s express high levels of the glial-derived neurotrophic factor receptor, which promotes autonomous IL-22 production ¹⁰. Thus, neurotropic factors may potentially modulate IL-22 production in cells in the periphery and thereby stimulate tissue and/or neuronal repair. Interestingly, IL-17 family cytokines adopt a cysteine knot structure that resembles nerve growth factor (NGF) ¹¹, hinting at possible crosstalk with the nervous system, but the significance of this homology is unclear. Apart from IL-17RA, the receptor subunits and downstream signaling pathways engaged by IL-17 on neurons remain largely undefined. Given the unique nature of the IL-17 cytokine family, it is likely that many more surprises will follow Enamorado et al.’s findings and further enhance our understanding of how IL-17 gets on one’s nerves.