Neurogenic inflammation and itch in barrier tissues.

Once regarded as distinct systems, the nervous system and the immune system are now recognized for their complex interactions within the barrier tissues. The neuroimmune circuitry comprises a dual-network system that detects external and internal disturbances, providing critical information to tailor a context-specific response to various threats to tissue integrity, such as wounding or exposure to noxious and harmful stimuli like pathogens, toxins, or allergens. Using the skin as an example of a barrier tissue with the polarized sensory neuronal responses of itch and pain, we explore the molecular pathways driving neuronal activation and the effects of this activation on the immune response.

A γδ T cell-IL-3 axis controls allergic responses through sensory neurons.

In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch. Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown.

Neuroimmune recognition of allergens.

Interactions between the nervous system and the immune system play crucial roles in initiating and directing the type 2 immune response. Sensory neurons can initiate innate and adaptive type 2 immunity through their ability to detect allergens and promote dendritic cell and mast cell responses. Neurons also indirectly promote type 2 inflammation through suppression of type 1 immune responses.

Sensory sentinels: Neuroimmune detection and food allergy.

Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization.

Sensory neuronal control of skin barrier immunity.

Peripheral sensory neurons recognize diverse noxious stimuli, including microbial products and allergens traditionally thought to be targets of the mammalian immune system. Activation of sensory neurons by these stimuli leads to pain and itch responses as well as the release of neuropeptides that interact with their cognate receptors expressed on immune cells, such as dendritic cells (DCs). Neuronal control of immune cell function through neuropeptide release not only affects local inflammatory responses but can impact adaptive immune responses through downstream effects on T cell priming.

A preliminary investigation of the simultaneous effects of cannabidiol and caffeine.

Caffeine and cannabidiol (CBD) are commonly consumed by the general population, particularly among young adults; however, there is little research on the simultaneous effects of caffeine and CBD. The present study aimed to examine the simultaneous self-reported effects of caffeine and CBD in young healthy adults. Participants ( = 54) who reported daily caffeine use (> 200 mg) attended one experimental session via Zoom and were assigned randomly to receive caffeine (200 mg) combined with either a placebo or CBD (25, 50, 80, 160, or 240 mg).

Novel and improved Caenorhabditis briggsae gene models generated by community curation.

Background: The nematode Caenorhabditis briggsae has been used as a model in comparative genomics studies with Caenorhabditis elegans because of their striking morphological and behavioral similarities. However, the potential of C. briggsae for comparative studies is limited by the quality of its genome resources.

Novel and improved gene models generated by community curation.

Background: The nematode has been used as a model for genomics studies compared to because of its striking morphological and behavioral similarities. These studies yielded numerous findings that have expanded our understanding of nematode development and evolution. However, the potential of to study nematode biology is limited by the quality of its genome resources.

Protease allergens as initiators-regulators of allergic inflammation.

Tremendous progress in the last few years has been made to explain how seemingly harmless environmental proteins from different origins can induce potent Th2-biased inflammatory responses. Convergent findings have shown the key roles of allergens displaying proteolytic activity in the initiation and progression of the allergic response. Through their propensity to activate IgE-independent inflammatory pathways, certain allergenic proteases are now considered as initiators for sensitization to themselves and to non-protease allergens.

Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic.

Sensory neuron hyperexcitability is a critical driver of pathological pain and can result from axon damage, inflammation, or neuronal stress. G-protein coupled receptor signaling can induce pain amplification by modulating the activation of Trp-family ionotropic receptors and voltage-gated ion channels. Here, we sought to use calcium imaging to identify novel inhibitors of the intracellular pathways that mediate sensory neuron sensitization and lead to hyperexcitability.

Functional Recognition Theory and Type 2 Immunity: Insights and Uncertainties.

Type 2 immunity plays an important role in host defense against helminths and toxins while driving allergic diseases. Despite progress in understanding the biology of type 2 immunity, the fundamental mechanisms regulating the type 2 immune module remain unclear. In contrast with structural recognition used by pattern recognition receptors, type 2 immunogens are sensed through their functional properties.

Sensory neurons control the functions of dendritic cells to guide allergic immunity.

Dendritic cells of the innate immune system and sensory neurons of the peripheral nervous system are embedded in barrier tissues and gather information about an organisms' environment. While the mechanisms by which dendritic cells recognize and initiate adaptive immune responses to pathogens is well defined, how they sense allergens is poorly understood. Indeed, allergens induce dendritic cell maturation and migration in vivo, but not in vitro.

No pain, no gain: Sensory neurons heal a sunburn.

In a recent issue of Nature, Hoeffel et al. describe a novel pathway of sterile tissue repair utilizing a mouse model of sunburn. This wound healing pathway is coordinated by sensory neuron-derived TAFA4 that induces IL-10 production from Tim4 dermal macrophages to prevent sustained inflammation and the emergence of tissue fibrosis.

A decision tree model for neuroimmune guidance of allergic immunity.

The immune system defends the body from infectious and non-infectious threats. Distinct recognition strategies have evolved to generate antigen-specific immunity against pathogens or toxins versus antigen-independent tissue repair. Structural recognition, or the sensing of conserved motifs, guides the immune response to viruses, bacteria, fungi, and unicellular parasites.

The CysLTR receptor mediates leukotriene C-driven acute and chronic itch.

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC, LTD, and LTE, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC and its signaling through the CysLT receptor 2 (CysLTR) in itch.

Protocol for dissection and culture of murine dorsal root ganglia neurons to study neuropeptide release.

In this protocol, we provide step-by-step instructions for dissection and culture of primary murine dorsal root ganglia (DRG), which provide an opportunity to study the functional properties of peripheral sensory neurons . Further, we describe the analysis of neuropeptide release by ELISA as a possible downstream application. In addition, isolated DRGs can be used directly for immunofluorescence, flow cytometry, RNA sequencing or proteomic approaches, electrophysiology, and calcium imaging.

Inflammasomes within Hyperactive Murine Dendritic Cells Stimulate Long-Lived T Cell-Mediated Anti-tumor Immunity.

Central to anti-tumor immunity are dendritic cells (DCs), which stimulate long-lived protective T cell responses. Recent studies have demonstrated that DCs can achieve a state of hyperactivation, which is associated with inflammasome activities within living cells. Herein, we report that hyperactive DCs have an enhanced ability to migrate to draining lymph nodes and stimulate potent cytotoxic T lymphocyte (CTL) responses.

Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens.

Dendritic cells (DCs) of the cDC2 lineage initiate allergic immunity and in the dermis are marked by their expression of CD301b. CD301b dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information to activate and induce the migration of CD301b DCs to the draining lymph node (dLN).

Targeting Lymph Node Niches Enhances Type 1 Immune Responses to Immunization.

Generating robust CD4 T-helper cell type 1 (Th1) responses is essential for protective vaccine-induced type 1 immunity. Here, we examine whether immunization formulation associated with enhanced vaccine efficacy promotes antigen targeting and cell recruitment into lymph node (LN) niches associated with optimal type 1 responses. Immunization with antigen and Toll-like receptor agonist emulsified in oil leads to an increased differentiation of IFNγ/TNF-α polyfunctional Th1 cells compared to an identical immunization in saline.

Nerves of Steel: How the Gut Nervous System Promotes a Strong Barrier.

In this issue of Cell, Jarret et al., Lai et al., and Matheis et al.

The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response.

The migration of mature dendritic cells (DCs) into the draining lymph node (dLN) is thought to depend solely on the chemokine receptor CCR7. CD301b DCs migrate into the dLN after cutaneous allergen exposure and are required for T helper 2 (Th2) differentiation. We found that CD301b DCs poorly upregulated CCR7 expression after allergen exposure and required a second chemokine signal, mediated by CCR8 on CD301b DCs and its ligand CCL8, to exit the subcapsular sinus (SCS) and enter the lymph node (LN) parenchyma.

The Great Opportunity: Cultivating Scientific Inquiry in Medical Residency.

Residency training is a profound experience that greatly influences the career trajectory of every trainee. Currently, residency programs focus heavily (or almost exclusively) on the acquisition of medical knowledge and fail to foster intellectual curiosity and introduce residents to careers in investigation. We share 3 programs embedded in residency training where this focus is shifted with an emphasis on prompting intellectual curiosity and exciting residents about careers in investigation to revitalize the physician-scientist workforce.

Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity.

Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters.