For reasons not fully understood, proresolving immune processes sometimes fail to engage after peripheral nerve injury (PNI), leading to enhanced neuropathic pain and inflammation. Here, we implicate reduced efferocytosis due to proteolytic cleavage of surface MER tyrosine kinase (MERTK) from macrophages at the site of PNI. After PNI, the proportion of macrophages expressing MERTK progressively decreased, while soluble (cleaved) MER increased. Using male and female knock-in mice encoding cleavage-resistant Mertk, we demonstrated that cleavage of MERTK from macrophages at the PNI site led to exaggerated pain-related behaviors. PNI-induced hyperactivity of TRPV1+ sensory neurons and damage to myelin and myelinated axons was exacerbated by MERTK cleavage. Cleavage of MERTK led macrophages to adopt a proinflammatory phenotype. It also reduced their efferocytotic capacity, increasing accumulation of TUNEL+(apoptotic) and RIPK3+ (necroptotic) cells at the injury site. The pronociceptive damage-associated molecular patterns (DAMPs) interleukin-33 and heat shock protein-90 were increased, consistent with passive release from uncleared cell corpses. These corpses can also release de novo antigens along with DAMPs to trigger autoimmunity, recently implicated in neuropathic pain through a mechanism involving secretion of immunoglobulin G (IgG). Indeed, MERTK cleavage led to accumulation of IgG at the injury site and dorsal root ganglia. All outcomes were further worsened when Mertk was conditionally deleted from macrophages. Our findings identify cleavage of MERTK from macrophages at the injury site as a pivotal regulator of pronociceptive and tissue-damaging neuroimmune signaling after PNI.

Although classically considered from a neuro-centric vantage point, is now well known that pain involves interaction between the immune and nervous systems. Neuro-immune interactions occur all along the pain axis from the tissues to the peripheral neurons, the dorsal root ganglia, the spinal cord and supraspinal centres. Immune cells from mast cells, macrophages, T cells and B cells, to the Schwann cells of neurons, and the glia cells in the spinal cord and brain, release diverse inflammatory mediators including cytokines and chemokines. Fundamental mechanisms underlying pain enhancement by immune cells are diverse and differ between nociceptive, neuropathic and nociplastic pain conditions. The involvement of the immune system in pain provides enormous potential for interventions to address pain by targeting these mechanisms. These interventions include pharmacological and genetic treatments, as well as non-pharmacological treatments with the potential to impact systemic and CNS immune activity, such as exercise, diet and treatments targeting psychosocial and behavioural features (e.g., sleep and stress). Logically, treatment efficacy should depend on matching the treatment to the relevant neuro-immune mechanism. The aim of this review is to provide a foundation to understand the relevance of neuro-immune interactions to the development and persistence of chronic pain, and its implications for treatment. We provide an overview of the role of neuroinflammation in pain, evidence that this contributes to human pain conditions, and how this can guide matching the right treatments to the right person.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of the antioxidant response pathway and an attractive target for treating diseases driven by oxidative stress, such as peripheral neuropathy. While activation of NRF2 by monomethyl fumarate (MMF) is well established, the systemic exposure and broad side-effect profile of MMF and its two FDA-approved prodrugs, diroximel fumarate and dimethyl fumarate, limit their broader therapeutic utility. To address this limitation, we present a series of α-keto ester-functionalized prodrugs of MMF (1-21), designed to release therapeutically active MMF selectively at the site of oxidative stress. These prodrugs were designed to exploit elevated pathological levels of reactive oxygen species (ROS), which trigger Baeyer-Villiger oxidation of the α-keto ester moiety, resulting in rapid hydrolysis of the generated anhydride and localized MMF release. Multiple α-keto esters (1-11, 13-16, and 18-21) demonstrated activity relative to MMF in our in vitro NRF2 reporter cell assay, but only in the presence of H2O2. Furthermore, structure-property relationship (SPR) analysis revealed that prodrugs with simple alkyl α-keto esters demonstrated the highest levels of NRF2 activation and therapeutic efficacy. Specifically, α-keto esters 4, 5, and 6, functionalized with trideutero methyl, ethyl, and iso-propyl esters, respectively, exhibit strong tissue-specific NRF2 activation in vivo, where 4 demonstrated full reversal of mechanical allodynia in a mouse model of neuropathy. These findings firmly establish α-keto ester prodrugs of MMF as a next-generation NRF2-targeting modality that overcomes the systemic exposure and off-target liabilities of existing fumarate therapies by exploiting pathological ROS as a trigger.

The skull bone marrow (SBM) is emerging as a critical hub for neuroimmune signaling, yet its role in chronic pain is unknown. Using integrated positron emission tomography/magnetic resonance imaging, here, we show that the levels of 18-kilodalton translocator protein (TSPO), a putative marker of immune cell density, are elevated in the SBM of individuals with chronic pain [n = 125; chronic low back pain (cLBP), n = 88; knee osteoarthritis (KOA), n = 37] compared with healthy controls (n = 22). These elevations were widespread, generally more pronounced for KOA than cLBP, associated with pain and pain-comorbid symptoms in partially segregated spatial patterns, and supported by preliminary immunohistochemical evidence in human SBM samples from a donor with a history of chronic pain (compared with a healthy donor). Because TSPO is highly expressed in myeloid cells, these results link SBM immune dysregulation with chronic pain and its associated psychological and functional impairments. These findings provide a strong rationale for investigating this previously overlooked structure, which remains largely underexplored in the context of pain.

ABSTRACT B cell-derived IgG in the dorsal root ganglia (DRG) drives neuropathic pain after peripheral nerve injury (PNI), but the site of B cell organization is unclear. Here, PNI induced leukocyte clusters in the DRG meninges, enveloped by lymphatic endothelium and apposed to high endothelial venules. These clusters resemble tertiary lymphoid structures (TLSs) with germinal center-like features, including germinal center B cells and plasma cells, and follicular dendritic and follicular helper T cells. Single-cell RNA sequencing revealed enrichment of germinal center B cells in the DRG meninges after PNI. Germinal center B cells regulate TLS organization: TLSs were absent after deletion of Ezh2 from germinal center-experienced B cells. Intrathecal CD20 monoclonal antibody to locally deplete B cells also disrupted TLS organization. Conversely, intrathecal B cell transfer to B cell-deficient (muMT) mice was sufficient for TLS organization after PNI. Allodynia did not develop when TLS organization was disordered. Similar TLSs formed in pig DRG after tail docking and in human donors with chronic pain, where B cell receptor clonotype analysis confirmed functional maturity. Together, these data establish that germinal center B cells are required for TLS organization, and that disrupting this process abolishes the development of neuropathic pain after PNI.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of the antioxidant response pathway and an attractive target for treating diseases driven by oxidative stress, such as peripheral neuropathy. While activation of NRF2 by monomethyl fumarate (MMF) is well established, the systemic exposure and broad side-effect profile of MMF and its two FDA-approved prodrugs, diroximel fumarate and dimethyl fumarate, limit their broader therapeutic utility. To address this limitation, we present a series of alpha-keto ester-functionalized prodrugs of MMF (1-21), designed to release therapeutically active MMF selectively at the site of oxidative stress. These prodrugs were designed to exploit elevated pathological levels of reactive oxygen species (ROS), which trigger Baeyer-Villiger oxidation of the alpha-keto ester moiety, resulting in rapid hydrolysis of the generated anhydride and localized MMF release. Multiple alpha-keto esters (1-11, 13-16, and 18-21) demonstrated activity relative to MMF in our in vitro NRF2 reporter cell assay, but only in the presence of H2O2. Furthermore, structure-property relationship (SPR) analysis revealed that prodrugs with simple alkyl alpha-keto esters demonstrated the highest levels of NRF2 activation and therapeutic efficacy. Specifically, alpha-keto esters 4, 5, and 6, functionalized with trideutero methyl, ethyl, and iso-propyl esters, respectively, exhibit strong tissue-specific NRF2 activation in vivo, where 4 demonstrated full reversal of mechanical allodynia in a mouse model of neuropathy. These findings firmly establish alpha-keto ester prodrugs of MMF as a next-generation NRF2-targeting modality that overcomes the systemic exposure and off-target liabilities of existing fumarate therapies by exploiting pathological ROS as a trigger.

Colorectal cancer survivors are at increased risk of developing neurological issues, particularly peripheral neuropathy and chronic pain. Although pre-existing neuropathy is a risk factor for chronic pain, tumor-induced neuropathy has not been firmly established in pre-clinical models. Consistent with clinical observations, we show that mice with colorectal cancer develop peripheral neuropathy, which was associated with subtle locomotor deficits, without overt hypersensitivity. We detected widespread differences in pro-inflammatory cytokines and lipid metabolites in peripheral nerves from tumor-bearing mice. Macrophage accumulation, myelin decompaction and ryanodine receptor oxidation were associated with dysfunctional calcium homeostasis and reduced spike amplitude in sensory neurons. Similar alterations in plasma inflammatory mediators and lipid metabolites were associated with neuropathy and macrophage accumulation in peripheral nerves of rhesus macaques with colorectal cancer. These findings suggest colorectal cancer is causally linked to a subacute form of chronic inflammatory demyelinating polyneuropathy across species, which may represent an under-reported, yet important risk factor for neurological dysfunction in colorectal cancer survivors. Whether cancer damages peripheral nerves before treatment is unclear. Here, authors show that colorectal tumors drive inflammation and disrupt neuronal lipids, causing subtle sensory pathology in mice and monkeys that may persist in survivors.

Injury to somatosensory nerves can lead to neuropathic pain. We recently identified that B cells play a crucial role in the development of neuropathic pain through a mechanism involving secreted immunoglobulin G (IgG) signaling at Fc gamma receptors (FcγRs). Here, we demonstrate that Fc gamma receptor IIa (FcγRIIa), expressed by astrocytes in the spinal cord, contributes to the development of mechanical allodynia after nerve injury in male and female rats. Following unilateral chronic constriction injury (CCI) of the sciatic nerve, Fcgr2a gene transcription increased specifically in the ipsilateral dorsal horn of the spinal cord, but remained unaltered in the dorsal root ganglia (DRGs) and contralateral spinal cord. FcγRIIa immunoreactivity increased in the ipsilateral spinal dorsal horn after CCI, and its expression colocalized primarily with GFAP+ astrocytes. Genetic disruption of Fcgr2a in GFAP-expressing spinal astrocytes using adeno-associated virus (AAV)-mediated CRISPR-Cas9 gene editing attenuated mechanical allodynia for weeks after CCI. In purified cultures of primary astrocytes, IgG immune complexes (IgG-IC) increased transcription of proinflammatory cytokines and chemokines. Expression of these cytokines and chemokines was reduced by siRNA-mediated knockdown of Fcgr2a, or by inhibition of the FcγRIIa effectors spleen tyrosine kinase (Syk) or nuclear factor-κB (NF-κB). These data suggest that FcγRIIa expressed by spinal astrocytes are activated following peripheral nerve injury and may directly contribute to injury-induced tactile pain through the release of proinflammatory mediators. These findings expand our understanding of how neuroimmune signaling from astrocytes contributes to the development of mechanical allodynia. PERSPECTIVE: Activation of FcγRIIa signaling in spinal astrocytes promotes mechanical allodynia following nerve injury and initiates neuroinflammatory pathways in response to IgG immune complexes. These findings reveal autoantibody IgG signaling at glial Fcγ receptors as a potential therapeutic approach to alleviate neuropathic pain.

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes pain hypersensitivity in mice by stimulating the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and subsequently activating the integrated stress response (ISR). We first established that Zucker Diabetic Fatty (ZDF) rats have enhanced MGO signaling, engage the ISR, and develop pain hypersensitivity. Since nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of antioxidant proteins that neutralize MGO, we hypothesized that fumarates, like diroximel fumarate (DRF), will stimulate Nrf2 signaling, and prevent MGO-induced ISR and pain hypersensitivity. DRF (100 mg/kg) treated animals were protected from developing MGO (20 ng) induced mechanical and cold hypersensitivity. Mechanistically, DRF treatment protected against MGO-induced increase in p-eIF2α levels in the sciatic nerve and reduced loss of intraepidermal nerve fiber (IENF) density. Using Nrf2-knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. Co-treatment of MGO (1µM) with monomethyl fumarate (MMF) (10, 20, 50 µM), the active metabolite of DRF, prevented the ISR in both mouse and human DRG neurons. Our data show that targeting Nrf2 with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.

Meningeal immune cells have recently emerged as critical modulators of neural function in both physiological and pathological states1,[2][1]. In particular, immune cells within the meninges surrounding the dorsal root ganglia (DRG) have been implicated in the pathogenesis of neuropathic pain[3][2]–[5][3]. Yet, the cellular complexity of the meningeal immune landscape and the neuroimmune interactions linking this niche to neuropathic pain remain poorly understood. Here, we show that peripheral nerve injury induces both the recruitment of leukocytes to the DRG meninges and their transcriptional reprogramming across innate (primarily myeloid cells) and adaptive immune compartments. The accumulation of myeloid cells, predominantly neutrophils and classical monocytes, within the DRG meninges originates from local vertebral bone marrow (BM) emergency myelopoiesis, followed by their migration through ossified vertebral channels. Further analysis identified meningeal granulocyte-macrophage colony- stimulating factor (GM-CSF), produced mainly by group 2 innate lymphoid cells (ILC2s), as a key mediator that instructs vertebral BM emergency myelopoiesis after peripheral nerve injury, thereby promoting neuropathic pain. These findings uncover a fundamental process linking meningeal immunity to vertebral BM emergency myelopoiesis in the pathophysiological cascade of neuropathic pain and highlight meningeal GM-CSF as the instructive signal orchestrating this neuroimmune axis. ### Competing Interest Statement TMC received research support from GSK. JRFH, ECE, JES, and CDE are current or previous employees of the GSK group of companies and may own GSK shares and/or restricted GSK shares. FMRP-USP/GSK-UK [1]: #ref-2 [2]: #ref-3 [3]: #ref-5

Neuropathic pain involves disruptions in sensory, cognitive, and affective processing, with microglial reactivity playing a crucial role in its development. While spinal microglial changes post-injury are well-documented, the time-dependent patterns of microglial reactivity in the brain remain unclear. This study aimed to characterize microglial morphological changes over time following peripheral nerve injury. Adult male and female Sprague-Dawley rats underwent chronic constriction injury (CCI) or sham surgery to the sciatic nerve, and brains were collected at 7 or 28 days post-surgery. CD11b immunostaining was used to visualize microglia across 52 brain regions linked to sensory, affective, and cognitive pain modalities. Morphological measures-including reactivity score, area, and length-were quantified with HALO software. A repeated-measures linear mixed model revealed significant effects of injury and timepoint on all parameters. Post hoc analyses identified region-specific changes (FDR-adjusted) in areas such as the anterior cingulate cortex, central amygdala, dorsal raphe, and dorsomedial hypothalamus, highlighting spatial specificity of microglial responses. A functional circuit-wide correlation network analysis showed a dynamic reorganization of microglial morphology following injury. Initially, at day 7, the primary motor cortex emerged as a hub, reflecting acute sensorimotor changes. By day 28, network hubs had shifted to the dorsomedial hypothalamus and ventral tegmental area, suggesting engagement of homeostatic and reward circuits in chronic pain. Graph-theoretic metrics revealed a progressive decline in global network connectivity over time, supporting the view that chronic neuropathic pain alters central microglial signaling in a region- and circuit-specific manner, relevant to pain chronification and its comorbidities. PERSPECTIVE: This article presents a comprehensive mapping of microglial morphology in brain areas associated with pain processing. The findings will guide further investigations into the ways in which microglia contribute to neuropathic pain and its comorbidities.

Chemotherapy-induced cognitive impairments (CICI), colloquially known as “chemobrain,” represents a profound and debilitating side effect experienced by a significant number of cancer survivors, impacting their memory, multitasking, and quality of life. This review critically evaluates the molecular mechanisms underlying CICI, with a particular focus on the insights gained from transcriptomic analyses. As cancer incidence rises globally, understanding the complex interplay between chemotherapy agents and their cognitive repercussions becomes increasingly vital. Key mechanisms implicated in CICI include blood-brain barrier disruption, neuroinflammation, and oxidative stress as a result of various chemotherapy treatments, such as doxorubicin, cisplatin, and paclitaxel. We delve into advanced transcriptomic methodologies including RNA sequencing, cDNA microarrays, and single-cell transcriptomics that elucidate the alteration in gene expression profiles associated with CICI and provide a deeper understanding of the underlying pathophysiological processes. Furthermore, we emphasize the importance of developing comprehensive single-cell atlases and employing spatial transcriptomics to uncover cellular heterogeneity and the spatial dynamics of gene expression across different brain regions. This review consolidates the existing literature on the transcriptomic profile of CICI, highlighting potential genes and pathways while suggesting future research avenues aimed at mitigating cognitive dysfunction. Ultimately, integrating transcriptomic findings with clinical insights is essential for the development of targeted, personalized interventions, thereby improving cognitive health and overall quality of life for cancer survivors dealing with long-term impacts of their treatment.

B cells contribute to the development of pain after sciatic nerve chronic constriction injury (CCI) via binding of immunoglobulin G (IgG) to Fc gamma receptors (FcγRs) in the lumbar dorsal root ganglia (DRG) and spinal cord. Yet the contribution of B cells to pain after different types of peripheral nerve injury is uncertain. Using male and female mice, we demonstrate a divergent role for B cell-IgG-FcγR signaling underlying mechanical allodynia between CCI, nerve crush (NC), spared nerve injury (SNI), and spinal nerve ligation (SNL). Depletion (monoclonal anti-CD20) or genetic deletion (muMT mice) of B cells prevented development of allodynia following NC and CCI, but not SNI or SNL. In apparent contradiction, circulating levels of autoreactive IgG and circulating immune complexes were increased in all models, though more prominent following NC and CCI. Passive transfer of IgG from SNI donor mice induced allodynia in CCI muMT recipient mice, demonstrating that IgG secreted after SNI is pronociceptive. To investigate why pronociceptive IgG did not contribute to mechanical allodynia after SNI, we evaluated levels of the Fc receptor γ subunit. SNI or SNL did not increase γ subunit levels in the DRG and spinal cord, whereas CCI and NC did, in agreement with B cell-dependent allodynia in these models. Together, the results suggest that traumatic peripheral nerve injury drives secretion of autoreactive IgG from B cells. However, levels of cognate FcγRs are increased following sciatic nerve constriction and crush, but not transection, to differentially regulate pain through the B cell-IgG-FcγR axis.

The skull bone marrow is emerging as a critical hub for neuroimmune signaling, yet its role in chronic pain is unknown. Using integrated positron emission tomography / magnetic resonance imaging, here we show that the levels of 18 kDa translocator (TSPO), a marker of immune cell density, is elevated in the skull bone marrow of individuals with chronic pain (N=125; chronic low back pain [cLBP], N=88; knee osteoarthritis [KOA], N=37), compared to healthy controls (N=22). These elevations were widespread, generally more pronounced for KOA than cLBP, and associated with greater pain intensity, pain interference, depression, and anxiety (all p < 0.001). Because TSPO is highly expressed in myeloid cells, these results associate skull bone marrow immune dysregulation with chronic pain and its associated psychological and functional impairments. These findings provide a strong rationale for investigating this previously overlooked structure, which remains largely underexplored in the context of pain. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the National Institute of Neurological Disorders and Stroke (1R01NS094306-01A1;1R01NS095937-01A1) and the National Institute on Drug Abuse (5R01DA053316-05).This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of Massachusetts General Hospital gave approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [F-18]-PBR06 radioligand to measure TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.

Dr. Linda R. Watkins, a Distinguished Professor at the University of Colorado Boulder, fundamentally altered the understanding of pain and neuroimmune signaling. As she concludes her tenure as Associate Editor of Brain, Behavior, and Immunity, this tribute reflectson her revolutionary discoveries. She pioneered the concept that glial cells actively participate in pain states, challenging neuron-centric dogma. Her work elucidated the roles of cytokines like IL-1β and IL-10, the chemokine fractalkine (CX3CL1), and the Toll-Like Receptor 4 (TLR4) in glial reactivity, sickness behavior, and unwanted opioid effects (tolerance, hyperalgesia). As a dedicated mentor and collaborator, particularly with Steve Maier, she fosters interdisciplinary research. Watkins champions translational science, co-founding Xalud Therapeutics to develop immune therapies like IL-10 gene therapy, leaving a profound legacy in neuroscience.

Neural infiltration is a hallmark of malignancy and correlates with poor clinical outcomes in several cancers. Neuronal activity is emerging as a driver of cancer progression and pain, raising interests in nociceptors as potential therapeutic targets. Several cancers cause intractable pain and are innervated by sensory neurons, suggesting that nociceptor activity may both mediate pain and promote tumor progression. We used MPNST as a model to investigate how sensory neuron activity contributes to tumor growth. In vivo models were generated by engrafting mouse MPNST cells into the sciatic nerve of mice, followed by pain behavioral assays and tumor growth measurements. We selectively stimulated Aβ, Aδ, and C fibers to assess sensory neuron subtype-dependent effects on tumor progression. The transient receptor potential vanilloid 1 channel (TRPV1) antagonist, AMG9810, was used in vitro and in vivo to test the role of TRPV1⁺ nociceptors in tumor growth. Primary dorsal root ganglion (DRG) sensory neuron cultures were prepared for multielectrode array recordings, calcium imaging and co-culture with MPNST cells. MPNST-bearing mice exhibited hypersensitivity to mechanical and thermal pain stimuli and exhibited ongoing pain. MPNST-conditioned media increased sensory neuron activity, intracellular calcium concentration, and ATF3 expression in DRG neurons. Selective stimulation of C fibers, but not Aβ or Aδ fibers, enhanced tumor growth, which was blocked by AMG9810. Conditioned media from activated TRPV1⁺ DRG neurons increased MPNST cell growth in vitro, suggesting a role of neuronal activity-dependent paracrine factors in driving tumor cell growth. MPNST is a painful and aggressive cancer originating in the peripheral nerves. Our findings reveal a feedforward loop that MPNST cells increase TRPV1⁺ nociceptor activity, which further promotes tumor progression. Targeting nociceptors may offer a dual therapeutic benefit by alleviating cancer pain and limiting MPNST growth.

Strategies to advance the field of neuroimmunology by embracing its complexity via inclusion of its multidisciplinary properties were discussed at a meeting in Cold Spring Harbor. Attendees proposed fostering of open communications and funding of collaborations across disciplines, and the recognition that our understanding of the neuroimmune system requires interdisciplinary science.