THE ROLE OF THE IL-33–GROUP 2 INNATE LYMPHOID CELL (ILC2) AXIS IN THE DEVELOPMENT OF POST-HERPERTIC NEURALGIA.

Post-herpetic neuralgia is a painful condition associated with herpes zoster, which is caused by varicella-zoster virus (VZV) reactivation in the trigeminal and dorsal root ganglia (DRG). Despite being one of the most prevalent types of neuropathic pain, its underlying mechanisms and potential therapeutic targets remain unclear. In our previous studies, we demonstrated that group 2 innate lymphoid cells (ILC2s) are capable of promoting neuropathic pain in the spared nerve injury (SNI) model through the recruitment and accumulation of myeloid cells in the DRG meninges. Therefore, the aim of this study is to investigate the role of IL-33 signaling as an activating factor for ILC2s in the development of post-herpetic neuralgia. Cutaneous HSV-1 infection was established in C57BL/6 mice by skin scarification and hind paw inoculation (1×10⁶ PFU). Nociceptive behavior was assessed via von Frey testing. Infected mice exhibited sustained nociception from 3 to 18 days post-infection (dpi) relative to mock controls. Flow cytometry demonstrated increased CD11c⁺ and Ly6C^lowCX3CR1⁺ myeloid populations in the DRG of infected mice 9 dpi. As next steps, single-cell RNA sequencing (scRNA-seq) will profile IL-33 release and ILC2 activation in DRG and skin tissue. Furthermore, we will evaluate the IL-33/ST2 pathway using ST2^-/- and conditional knockout mice (Nmur1^iCreST2^fl/fl, Nmur1^iCreCsf2^fl/fl and Vav1^CreCsf2ra^fl/fl) to elucidate ILC2-driven myeloid recruitment, neuro-glial modulation, and mediator secretion (IL-4, IL-5, IL-13, AREG, GM-CSF). Lastly, pharmacological blockade via an ST2 inhibitor (ST2-IN-1) and anti-IL-33 antibody (itepekimab) will be tested to alleviate pain behaviors. Overall, our data demonstrate an accumulation of DRG myeloid cells at 9 dpi, consistent with peak pain severity, highlighting a possible envolviment of IL-33/ILC2 axis as a key mechanism.