Emerging mechanisms of ILC2 ‐neuronal crosstalk across the body

Emerging roles of ILC2 in neuronal crosstalk across organs. In a series of studies published in 2025, ILC2 were shown to regulate nervous system function across a range of organs across the body. Within the intestinal tract, ILC2-derived cytokines acted on enteric neurons to orchestrate immunity to helminths (Wang et al). Intestinal ILC2 are triggered to migrate to the pancreas via enteric neuronal-derived norepinephrine (NE), with pancreatic ILC2 mediating key roles in glucose homeostasis (Sestan et al). ILC2-derived cytokines in the dorsal root ganglia of the sciatic nerve controlled neurosensation to regulate gait and locomotor function (Deshpande et al), while in the central nervous system, ILC2 responses modulated neuronal synapse formation in early life to promote learning and memory (Steffen et al). In the context of stroke and neurotrauma, the ILC2 axis promoted tissue repair via actions on local stem cells (Liu et al). Together, these studies highlighted the emerging role of ILC2 neuroimmune crosstalk in health and disease. The past decade has revealed unprecedented crosstalk between the nervous system and immune system, implicating neuroimmune communication as a critical axis in a wide range of physiological processes.1-6 Tissue-resident immune cells sense a wide range of neuronal signals that regulate effector function, promote immunity, and maintain organ homeostasis; in turn, neurons within the central nervous system (CNS) and periphery can receive contextual cues from the immune system. Group 2 Innate Lymphoid Cells (ILC2s) are tissue-resident innate immune cells that have canonical roles in type 2 immunity, including expulsion of helminth infections and tissue repair.7 ILC2s respond rapidly to environmental cues by producing cytokines, including IL-5 and IL-13.7 A growing body of literature has demonstrated the capacity of ILC2s to integrate input from the nervous system.5, 6, 8 In addition, recent studies have begun to demonstrate reciprocal feedback, whereby ILC2-derived cytokines act directly on neurons to alter sympathetic and parasympathetic tone.1, 2, 4-6, 8 Here, we summarize a number of advances published in 2025 that reveal new insights into ILC2 interactions with neurons across the CNS, peripheral nervous system (PNS), and enteric nervous system (Figure 1). ILC2s evolved as one component of a suite of type 2 immune cells that mediate immunity to mucosal helminth infections. Wang et al.9 investigated how ILC2s and enteric neurons (ENs) converge to orchestrate robust antihelminth immunity. Following Nippostrongylus brasiliensis infection, the authors observed activation of a subset of ENs across the jejunum, associated with transcriptional changes including the upregulation of the genes encoding the neuropeptides NMU and β-Calcitonin Gene-Related Protein (β-CGRP), the cytokine Interleukin (IL)-7, and the cytokine receptor IL-13Rα. While both NMU and CGRP have been shown to be potent modulators of ILC2 responses,8 these observations suggested enteric neurons might directly sense ILC2-derived IL-13 upon activation. Utilizing transgenic animal models deficient in either neuronal-intrinsic IL-13Rα or ILC2s, they showed that ILC2-derived IL-13 was required to induce activation of jejunal ENs following infection. Notably, neuronal-intrinsic IL-13Rα expression was required for robust antihelminth responses, including optimal ILC2 expansion, goblet cell hyperplasia, and worm expulsion. Additionally, constitutive expression of IL-13Rα in ENs directly suppressed ILC2 responses to N. brasiliensis via β-CGRP. This work revealed a negative feedback loop, whereby ILC2-derived IL-13 induces ENs to release suppressive neuropeptides that in turn curtail ILC2 responses, potentially to prevent chronic inflammation and long-term tissue damage. While the enteric nervous system is thought to act in a semiautonomous manner, it receives inputs from the CNS via the vagus nerve. Whether such enteric ILC2-neuronal circuits are also influenced by the CNS remains unclear. Beyond their canonical roles in barrier immunity, ILC2s support a wider range of physiological processes across organs. Notably, ILC2s have been ascribed key roles in metabolic processes in tissues such as the liver and adipose tissue and can respond to nutritional cues both directly and via neuronal circuits.10 Šestan et al.11 hypothesized that the nervous and immune systems might cooperate to regulate glucose homeostasis to efficiently manage energy requirements for host defense. Using a model of transient fasting, the authors noted an increase in pancreatic ILC2s. To determine whether ILC2 could alter pancreatic function, they utilized mice lacking innate and adaptive lymphocytes, including ILC2s, and found these animals have lower blood glucose, higher glycogen, higher triglycerides, and reduced glucagon levels following fasting. During fasting, reduced levels of circulating glucose induce the release of glucagon by pancreatic alpha-cells, prompting the liver and muscle to break down glycogen. Simultaneously, triglycerides were metabolized to yield byproducts that can be converted to glucose. Reintroducing ILC2s restored glucose homeostasis, provoking the question as to whether ILC2s could regulate pancreatic alpha-cells. In vivo, fasting induced IL-13 and IL-5-producing ILC2s, and stimulation of pancreatic alpha-cells ex vivo with IL-5 and IL-13 led to the induction of glucagon secretion. Indeed, IL-5 and IL-13 were required for normal glucagon secretion by alpha-cells in vivo, indicating pancreatic ILC2 control glucose metabolism via their effector cytokines. Intriguingly, through the use of photoconvertible mice, Šestan et al.11 found the elevation in pancreatic ILC2 numbers upon fasting was due to migration from the small intestine. Strikingly, sympathetic neurons were required to induce ILC2 migration, with catecholaminergic enteric neurons directly determining ILC2 frequencies in the pancreas and consequently glucose metabolism. Mechanistically, norepinephrine (NE) licensed intestinal ILC2 migration via the beta 2 adrenergic receptor, demonstrating orchestration of ILC2 metabolic function via enteric neurons. This study identified a novel neuroimmune circuit that exemplifies the complexity of multiorgan systems required to maintain metabolic homeostasis. It remains to be seen whether similar neuroimmune axes operate in other metabolic tissues, such as the adipose or liver, or whether these neuronal networks interconnect with wider neuronal circuits that regulate energy balance systemically. Despite these advances, the consequences of ILC2-neuroimmune circuits for the activity of the nervous system itself have remained unclear. Deshpande et al.12 recently provided clear evidence that ILC2s modulate the peripheral nervous system. Specifically, they found the sciatic nerve (SN) was relatively enriched in ILC2s, alongside other nervous system tissues including the Dorsal Root Ganglia (DRG), dural meninges and brain. SN-associated ILC2s were transcriptionally distinct from those found at mucosal barrier sites, expressing genes associated with axonogenesis, neuron projection, glyogenesis, and myelination, suggesting SN-ILC2s might support neuroprotection and nerve development. The PNS, including the SN, acts to perceive stimuli via nociception, as well as coordinating fundamental locomotor behaviors, including gait. To understand whether SN-associated ILC2s contribute to PNS function, the authors employed an inflammatory pain model in the hind paw. Here, loss of ILC2s resulted in a higher degree of mechanical and thermal sensitivity and gait impairments, suggesting SN-associated ILC2s may normally temper nociceptor activity. To probe how ILC2s regulate SN neurons, the authors profiled the expression of receptors associated with ILC2 cytokines, and found SN neurons expressed both components of the IL-13 receptor. Genetic deletion of IL-4Rα, a subunit of the IL-13R, from neurons resulted in hypersensitivity to thermal and mechanical touch, while ex vivo cultures of SN neurons stimulated with IL-13 demonstrated a regenerative effect, increasing axon length. Finally, treatment with recombinant IL-13 was sufficient to restore hypersensitivity and gait deficits in ILC2-deficient mice. Together, this study identified a potential therapeutic avenue, exploiting neuroimmune interactions to treat peripheral neuropathologies. The emerging role of ILC2 neuroimmune circuits in the PNS raises the question as to whether similar circuits exist in the CNS, and how they differ from those in the periphery. Neuroimmune circuits have been described in the CNS, whereby dural meningeal-resident leukocyte-derived cytokines can shape complex behaviors and neurological function.13 ILC2s are particularly enriched in the dural meninges, have been implicated in neurodevelopment, and are present in the brain during neuroinflammation14 and aging.15 Nonetheless, their role at these sites in adults at homeostasis remains unclear. Steffen et al.16 asked whether ILC2s play a role in CNS neurodevelopment and murine behavior. Genetic depletion of ILC2s resulted in a reduction in hippocampal VGAT+ inhibitory synapses in early life. In adult mice, loss of inhibitory synapses resulted in deficient performance in hippocampal-dependent tasks such as learning and memory, suggesting ILC2s play a role in supporting neuronal function and raising the possibility that this may extend to wider neuronal and glial cell circuits across the brain. Indeed, these findings complement a previous study that showed ILC2-derived IL-13 is required to maintain inhibitory interneuron synapses in the primary somatosensory cortex and medial prefrontal cortex.17 Beyond neurodevelopment, an understanding of neuroimmune interactions in the CNS has important implications for neurodegeneration and neuroinflammatory diseases. Stroke, a condition that affects nearly 20% of individuals globally, is characterized by neuronal damage and severe behavioral and cognitive sequelae.18 One recent study investigated the neuroimmune contributions to brain tissue repair following stroke. Using middle cerebral artery occlusion (MCAO) to model stroke in mice, Liu et al.19 observed a robust increase in cerebral and dural ILC2s and a robust increase in IL-5 and IL-13. Immunofluorescence imaging of the brain found ILC2s localized at the lesion site. Notably, in the absence of ILC2s, mice exhibited more severe motor deficits and neurological disease burdens following stroke, suggesting ILC2s may support repair. Indeed, adoptive transfer of ILC2s into ILC2-deficient hosts improved stroke outcome and reduced clinical severity. ILC2s were potent producers of the growth factor Amphiregulin (Areg) in the brain, and Areg was identified to be critical for poststroke repair. In ILC2-deficient mice, three distinct populations of neural stem cell precursors were found to be reduced. ILC2s cocultured with brain organoids in vitro yielded larger spheroids, while the addition of Areg, but not IL-13 or IL-5, increased the proliferation of neural stem cells. In line with this, ILC2-derived Areg alleviated poststroke functional neurological deficits and increased the proliferation of neural stem cells in vivo. Together, these studies identify novel roles for brain-associated ILC2s as neuroprotective and reparative sentinels in the CNS. These recent studies reveal novel neuroimmune circuits involving ILC2s and their cytokines across a range of tissues and fundamental physiological processes, and spanning both immune and neurological function. More broadly, these findings complement a larger body of research that implicates interactions between the nervous system and immune system as critical in maintaining health and preventing disease. Harnessing this information has the potential to open exciting new therapeutic avenues for clinical intervention. Research in the Hepworth lab is supported by a Wellcome Trust Career Development Award [227760/Z/23/Z] (MRH). The authors have no competing financial interests to declare.