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Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund’s adjuvant (CFA) as a model of adjuvant- and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G⁺CD11b⁺ neutrophils and T-cell receptor (TCR) β⁺ T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b⁺Ly6G⁻ myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2⁺Ly6Chi) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b⁺Ly6G⁻ myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.

The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4+SNS-Cre/TdTomato+, 2) IB4−SNS-Cre/TdTomato+, and 3) Parv-Cre/TdTomato+ cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation. In the nervous system, a network of specialized neurons—known as the somatosensory system—carries information about sensations including touch, muscle position, temperature and pain. Distinct sets of somatosensory neurons are thought to carry information about the different types of sensations. In young animals, the precise switching on, or ‘expression’, of genes controls the formation of the network of neurons. However, it is not known exactly which genes are expressed in what types of neurons, where, or when. Here, Chiu et al. used a technique called flow cytometry using different fluorescent markers to isolate a group of cells called Dorsal Root Ganglion (DRG) neurons in mice. These neurons have long thread-like fibers that extend from the spinal cord to the skin, muscles and joints all over the body. These fibers carry sensory information to the spinal cord, where it can be relayed to the brain and processed. The experiments compared three distinct types of DRG neuron and found that they differed in their ability to send information to other cells. Chiu et al. analyzed the expression of all the genes in the three types of DRG neurons. Each type of neuron had distinct groups of genes that were being expressed. Also, several genes that are known to be important for sensation were expressed at different levels in the different types of cells. Next, large numbers of single cells were analyzed to find out the finer details about the three types of neuron. These findings made it possible to further divide the DRG neurons into six distinct subsets that matched previously known groups of somatosensory neurons, and also identified new ones. Chiu et al.'s findings reveal the complexity and diversity of the neurons involved in carrying information about sensations towards the brain. This is an important step in classifying the nervous system, and uncovers many genes previously not linked to sensation. The next challenges lie in understanding how the expression of these genes in each type of neuron relates to their unique roles.

B-cell activation triggers the release of endoplasmic reticulum calcium stores through the store-operated calcium entry (SOCE) pathway resulting in calcium influx by calcium release-activated calcium (CRAC) channels on the plasma membrane. B-cell-specific murine knockouts of SOCE do not impact humoral immunity suggesting that alternative channels may be important. We identified a member of the calcium-permeable transient receptor potential (TRP) ion channel family, TRPV5, as a candidate channel expressed in B cells by a quantitative polymerase chain reaction (qPCR) screen. To further investigate the role of TRPV5 in B-cell responses, we generated a murine TRPV5 knockout (KO) by CRISPR-Cas9. We found TRPV5 polarized to B-cell receptor (BCR) clusters upon stimulation in a PI3K-RhoA-dependent manner. TRPV5 KO mice have normal B-cell development and mature B-cell numbers. Surprisingly, calcium influx upon BCR stimulation in primary TRPV5 KO B cells was not impaired; however, differential expression of other calcium-regulating proteins, such as ORAI1, may contribute to a compensatory mechanism for calcium signaling in these cells. We demonstrate that TRPV5 KO B cells have impaired spreading and contraction in response to membrane-bound antigen. Consistent with this, TRPV5 KO B cells have reduced BCR signaling measured through phospho-tyrosine residues. Lastly, we also found that TRPV5 is important for early T-dependent antigen specific responses post-immunization. Thus, our findings identify a role for TRPV5 in BCR signaling and B-cell activation.

Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it resulted from a lack of motor end plate reinnervation. Tg mice expressing high levels of Hsp27 demonstrated enhanced restoration of motor function after nerve transection/resuture by enabling motor synapse reinnervation, but only within 5 weeks of injury. In humans with peripheral nerve injuries, shorter wait times to decompression surgery led to improved functional recovery, and, while a return of sensation occurred in all patients, motor recovery was limited. Thus, absence of motor recovery after nerve damage may result from a failure of synapse reformation after prolonged denervation rather than a failure of axonal growth.

IntroductionMultiple sclerosis (MS) is a chronic autoimmune neurological disease with a variable prognosis and unpredictable course. Fatigue, pain and low mood are common symptoms that tend to fluctuate in people with MS (pwMS). Disrupted circadian rhythms may have a role in the symptoms’ variability. Distinguishing interindividual differences and temporal daily fluctuations in MS symptoms may help to define specific symptomatic phenotypes. Understanding how these phenotypes are associated with quality of life and their immunological underpinnings—immune profiles—could shape new MS management strategies. Our primary aim is to document ongoing fluctuations in fatigue, pain and mood in a cohort of pwMS to determine whether symptom variability is associated with differential quality of life. Our secondary aim is to evaluate the feasibility of our study design to identify immune profiles of circadian rhythmicity in MS.Methods and analysisThis observational cohort study examines individual temporal fluctuations in MS symptomatology via ecological momentary assessment in a cohort of pwMS. All participants complete (1) a baseline battery of questionnaires and (2) electronic symptom-tracking diaries to rate fatigue, pain intensity and mood on a 0–10 scale at three time points (08:00, 14:00 and 20:00) for 10 days. Participants will be grouped into symptomatic phenotypes based on longitudinal data from e-diaries. We will assess whether exhibiting a specific phenotype is associated with certain baseline measures. A subgroup of 20 participants—feasibility study—will also complete blood sample collection two times within 24 hours to study immune profiles and molecular markers of circadian rhythmicity in MS. Flow cytometry, whole blood RNA sequencing and plasma analyses will be applied to determine changes in immune profiles indicative of circadian rhythmicity.This work has the potential to reduce the burden of this complex disease on a global scale. Future studies will build on our work to understand individual variability in MS symptomatology, including disease severity; identification of biomarkers underlying the association between rhythmic symptomatology profiles and symptomatic phenotypes in MS; and designing personalised interventions focused on interindividual differences in symptomatology and circadian rhythmicity.Ethics and disseminationThe CircaMS project and its associated procedures have been reviewed and approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals research ethics board (File number: 6039383). Participants provide informed consent to participate, and their data will not be identifiable in any publication or report. All documents are stored securely and only accessible by study staff and authorised personnel. The results will be presented to academic and lay audiences via national/international conferences, publications in peer-reviewed journals, social media and through an official website created to engage pwMS, caregivers, clinicians and researchers.

IntroductionOne in five Canadians lives with chronic pain. Evidence shows that some individuals experience pain that fluctuates in intensity following a circadian (24-hour) rhythm. Endogenous molecular rhythms regulate the function of physiological processes that govern pain mechanisms. Addressing chronic pain rhythmicity on a molecular and biopsychosocial level can advance understanding of the disease and identify new treatment/management strategies. Our CircaHealth CircaPain study uses an online survey combined with ecological momentary assessments and biosample collection to investigate the circadian control of chronic pain and identify potential biomarkers. Our primary objective is to understand interindividual variability in pain rhythmicity, by collecting biopsychosocial measures. The secondary objective accounts for seasonal variability and the effect of latitude on rhythmicity.Methods and analysisFollowing completion of a baseline questionnaire, participants complete a series of electronic symptom-tracking diaries to rate their pain intensity, negative affect, fatigue and stress on a 0–10 scale at 8:00, 14:00 and 20:00 daily over 10 days. These measures are repeated at 6 and 12 months postenrolment to account for potential seasonal changes. We aim to recruit ≥2500 adults with chronic pain within Canada. Infrastructure is being developed to facilitate the collection of blood samples from subgroups of participants (~800) two times per day over 24–48 hours to identify rhythmic expression of circulating genes and/or proteins.Ethics and disseminationEthical approval for this study was obtained by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (File No. 6038114). Participants provide informed consent to participate, and their data will not be identifiable in any publication or report. Findings will be published in a relevant scientific journal and disseminated at scientific meetings and online webinars. We maintain a website to post updated resources and engage with the community. We employ knowledge mobilisation in the form of direct data sharing with participants.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia in adults. It is well-established that CADASIL results in neurocognitive dysfunction and mood disturbance. There is also cumulative evidence that CADASIL patients are more susceptible to ischemic heart disease. The aim of this study is to review the current literature regarding the incidence of coronary artery disease in CADASIL patients with a focus on the various management options and the clinical challenges associated with each of these treatment strategies. We conducted a literature search using Cochrane, MEDLINE, and EMBASE for papers that reported the occurrence of coronary artery disease in patients with CADASIL. We supplemented the search with a manual search in Google Scholar. Only case reports, case series, and original articles were included. The search resulted in six reports indicating the association between coronary artery disease and CADASIL and its management. Evidence suggests that extracranial manifestations of CADASIL may include coronary artery disease, presenting as a more extensive burden of disease in younger patients. Surgical and percutaneous revascularization strategies are feasible, but the incidence of peri-procedural stroke remains significant and should be weighed against the potential benefit derived from either of these strategies. A multidisciplinary approach to therapy, with perspectives from neurologists, cardiologists, and cardiac surgeons, is needed to provide the appropriate treatment to the CADASIL patient with severe coronary artery disease. Future studies should be directed toward the development of targeted therapies that may help with the early detection and prevention of disease progress in these patients.

Skin-resident γδ T cells play an important role in maintaining the immune barrier at the epithelial surface. Their roles in wound healing, regulation of immune response to injury, and reepithelialization have been characterized extensively in the mouse, though their function in human skin remains largely unknown. Human skin-resident γδ T cells sparsely populate the skin and are often small and rounded in appearance. Those in the mouse ear and back, which line the dermal barrier, are highly arborized cells with many processes extending from the cell body. To date, these cells have been studied primarily in the mouse ear and back; however, it is important to further identify and characterize γδ T cells in other body sites to better understand their function and study their contribution to injury and disease. We developed a novel method to visualize these cells in the skin (whole-mount and cryosections) that when combined with flow cytometry allowed us to assess differences in skin-resident γδ T cell numbers, morphology, and activation state in the ear, back, and footpad (chosen for their importance in immunological and pain research). In comparing cell length, number of dendritic processes, and expression of the activation marker CD69, we found that γδ T cell morphology and activation states vary significantly among the three tissue environments. Specifically, γδ T cells in the footpad are smaller, have fewer processes, and show the highest levels of activation compared to back- and ear-resident cells. Our observations suggest that our understanding of skin-resident γδ T cell functionality, drawn from the experiments performed in the ear and back tissue, may not be applicable to all skin environments. The footpad-resident cells also more closely resemble γδ T cells in human skin, suggesting that cells in this tissue environment may serve as a better translational model when studying γδ T cell function/activity.

Biological rhythms control gene expression, but effects on central nervous system (CNS) cells and structures remain poorly defined. While circadian (24-hour) rhythms are most studied, many genes have periods of greater and less than 24-hours; these fluctuations can be both site- and cell-specific. Identifying patterns of gene rhythmicity across the CNS is necessary for both the study of chronobiology and to make sense of data obtained in the laboratory. We now identify cycling mRNAs, miRNAs, gene networks and mRNA-miRNA co-expression pairs in the cortex, hypothalamus, and corpus striatum of male C57BL/6J mice using high-dimensional datasets. A searchable catalogue ( https://www.ghasemloulab.ca/chronoCNS ) helps refine the analysis of cellular and molecular rhythmicity across the CNS (using the liver as a control). Immunofluorescence confirms the rhythmicity of key targets across cells in these structures, with strong cycling signatures in resting oligodendrocytes. Our study sheds light on the contribution of diurnal, ultradian, and infradian rhythms and mRNA-miRNA interactions to CNS function. This study identifies cycling mRNAs, miRNAs, gene networks and mRNA-miRNA co-expression pairs in the cortex, hypothalamus, and corpus striatum, providing a searchable catalogue to help refine future analyses of the CNS.

IntroductionEvidence suggests a role for Central nervous system glia in pain transmission and in augmenting maladaptive opioid effects. Identification of drugs that modulate glia has guided the evaluation of glial suppression as a pain management strategy. This planned systematic review will describe evidence of the efficacy and adverse effects of glial-modulating drugs in pain management.Methods and analysisA detailed search will be conducted on the Cochrane Central Register of Controlled Trials, Medline, and Embase from their inception until the date the final searches are run to identify relevant randomised controlled trials. The reference lists of retrieved studies, as well as online trial registries, will also be searched. English language, randomised, double-blind trials comparing various glial-modulating drugs with placebo and/or other comparators, with participant-reported pain assessment, will be included. Two reviewers will independently evaluate studies for eligibility, extract data and assess trial quality and potential bias. Risk of bias will be assessed using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. Primary outcomes for this review will include any validated measure of pain intensity and/or pain relief. Dichotomous data will be used to calculate risk ratio and number needed to treat or harm. The quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation.Ethics and disseminationThis systematic review does not require formal ethics approval. The findings will be disseminated through peer-reviewed publications and conference presentations.PROSPERO registration numberCRD42021262074.