Research

Emerging studies reveal that neurotransmitters and neuropeptides play critical roles in regulating anti-helminth immune responses, hinting at the potential of intrinsic enteric neurons (iENs) in orchestrating intestinal immunity. Whether and how iENs are activated during infection and the potential neuroimmune interactions involved remain poorly defined. Here, we found that helminth infection activated a subset of iENs. Single-nucleus RNA sequencing (snRNA-seq) of iENs revealed alterations in the transcriptional profile of interleukin (IL)-13R+ intrinsic primary afferent neurons (IPANs), including the upregulation of the neuropeptide β-calcitonin gene-related peptide (CGRP). Using genetic mouse models and engineered viral tools, we demonstrated that group 2 innate lymphoid cell (ILC2)-derived IL-13 was required to activate iENs via the IL-13R, leading to iEN production of β-CGRP, which subsequently inhibited ILC2 responses and anti-helminth immunity. Together, these results reveal a previously unrecognized bi-directional neuroimmune crosstalk in the intestine between a subset of iENs and ILC2s, which influences pathogen clearance.

Group 3 innate lymphoid cells (ILC3s) play crucial roles in maintaining intestinal homeostasis and defending against bacterial infections. However, the epigenetic mechanisms that regulate ILC3 responses are not well understood. In this study, we show that Trmt61a, the methyltransferase responsible for the m1A58 tRNA modification, is predominantly expressed in ILC3s. We found that specific depletion of TRMT61A in ILC3s leads to dysregulated cell cycle and a reduction in cell numbers. Notably, mice with an ILC3-specific TRMT61A deficiency exhibit dysbiosis, but antibiotic treatment can restore colonic ILC3 levels. Furthermore, these mice exhibit increased susceptibility to experimental intestinal inflammation and enteric bacterial infection. Our findings uncover a previously unrecognized role for TRMT61A mediated m1A modification in the regulation of intestinal ILC3s, essential for protecting intestinal tissue during inflammation and enhancing innate immunity against enteric pathogens.