Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation.

Activation of dermal mast cells through the Mas-related G protein-coupled receptor B2 receptor (MrgprB2 in mice and MrgprX2 in humans) is a key component of numerous inflammatory skin diseases, including dermatitis and rosacea. Sensory neurons actively suppress mast cell activation through the regulated release of glutamate, resulting in reduced expression of as well as genes associated with proteins found in mast cell granules. To determine whether exogenous glutamate receptor agonism could suppress mast cell function, we determined that mast cells have relatively selective expression of the glutamate receptor ionotropic, kainate 2 (GluK2).

Melanomas and mast cells: an ambiguous relationship.

Mast cells (MCs) accumulate in a broad range of tumors, including melanomas. While MCs are potent initiators of immunity in infection, and in allergic inflammation, the function of MCs in anti-melanoma immunity is unclear. MCs have the potential to release tumoricidal cytokines and proteases, to activate antigen-presenting cells and to promote anti-tumor adaptive immunity.

Neuroimmune interactions in atopic and allergic contact dermatitis.

The skin is a barrier organ populated by many types of skin-resident immune cells and sensory neurons. It has become increasingly appreciated that neuroimmune interactions are an important component of inflammatory diseases such as atopic dermatitis and allergic contact dermatitis. Neuropeptides secreted from nerve terminals play an important role in mediating cutaneous immune cell function, and soluble mediators derived from immune cells interact with neurons to induce itch.

A microarray patch SARS-CoV-2 vaccine induces sustained antibody responses and polyfunctional cellular immunity.

Sustainable global immunization campaigns against COVID-19 and other emerging infectious diseases require effective, broadly deployable vaccines. Here, we report a dissolvable microarray patch (MAP) SARS-CoV-2 vaccine that targets the immunoresponsive skin microenvironment, enabling efficacious needle-free immunization. Multicomponent MAPs delivering both SARS-CoV-2 S1 subunit antigen and the TLR3 agonist Poly(I:C) induce robust antibody and cellular immune responses systemically and in the respiratory mucosa.

P2X7 Receptor Expression and Signaling on Dendritic Cells and CD4 T Cells is Not Required but Can Enhance Th17 Differentiation.

The purinergic receptor P2X7 (P2X7R) is important in inflammasome activation and generally considered to favor proinflammatory immune responses. However, there is still a limited understanding of the role of P2X7R signaling in Th cell differentiation, particularly, Th17 differentiation. Herein, the impact of P2X7R signaling on primary Th17 and Th1 cell responses was examined when P2X7R was expressed specifically on dendritic cells (DCs) and CD4 T cells.

Skin codelivery of contact sensitizers and neurokinin-1 receptor antagonists integrated in microneedle arrays suppresses allergic contact dermatitis.

Background: Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type 1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P and hemokinin 1, which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD.

Neuron‒Mast Cell Cross-Talk in the Skin.

Skin-resident mast cells (MCs) and cutaneous sensory neurons both play crucial roles in microbial‒host defense and inflammatory diseases. MCs can be directly activated by pathogens or their products, resulting in the release of numerous mediators that promote innate immune responses and also activate sensory neurons. Cutaneous sensory neurons can also directly detect the presence of pathogens, resulting in the release of neuropeptides that modulate MC function.

Electrophilic nitro-fatty acids suppress psoriasiform dermatitis: STAT3 inhibition as a contributory mechanism.

Psoriasis is a chronic inflammatory skin disease with no cure. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood, inflammation is a central mediator of disease progression. In this regard, electrophilic nitro-fatty acids (NO-FAs) exert potent anti-inflammatory effects in several in vivo murine models of inflammatory diseases, such as chronic kidney disease and cardiovascular disease.

Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.

Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models.

Microarray patches enable the development of skin-targeted vaccines against COVID-19.

The COVID-19 pandemic is a serious threat to global health and the global economy. The ongoing race to develop a safe and efficacious vaccine to prevent infection by SARS-CoV-2, the causative agent for COVID-19, highlights the importance of vaccination to combat infectious pathogens. The highly accessible cutaneous microenvironment is an ideal target for vaccination since the skin harbors a high density of antigen-presenting cells and immune accessory cells with broad innate immune functions.

MALT1 Protease Plays a Dual Role in the Allergic Response by Acting in Both Mast Cells and Endothelial Cells.

The signaling protein MALT1 plays a key role in promoting NF-κB activation in Ag-stimulated lymphocytes. In this capacity, MALT1 has two functions, acting as a scaffolding protein and as a substrate-specific protease. MALT1 is also required for NF-κB-dependent induction of proinflammatory cytokines after FcεR1 stimulation in mast cells, implicating a role in allergy.

Neurokinin-1 Receptor Signaling Is Required for Efficient Ca Flux in T-Cell-Receptor-Activated T Cells.

Efficient Ca flux induced during cognate T cell activation requires signaling the T cell receptor (TCR) and unidentified G-protein-coupled receptors (GPCRs). T cells express the neurokinin-1 receptor (NK1R), a GPCR that mediates Ca flux in excitable and non-excitable cells. However, the role of the NK1R in TCR signaling remains unknown.

Cutaneous immune responses mediated by dendritic cells and mast cells.

In the skin, complex cellular networks maintain barrier function and immune homeostasis. Tightly regulated multicellular cascades are required to initiate innate and adaptive immune responses. Innate immune cells, particularly DCs and mast cells, are central to these networks.

Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation.

T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells.

New dog and new tricks: evolving roles for IL-33 in type 2 immunity.

IL-33 is a more recently identified member of the IL-1 cytokine family, expressed in the nucleus of epithelial cells and released into the extracellular space following tissue damage. The impact of IL-33 as a regulator of the adaptive immune response has been studied extensively, with an understood role for IL-33 in the effector functions of CD4(+) Th2 cells. IL-33, however, is now being shown to initiate the Th2-polarizing function of DCs, and stimulate the secretion of the type 2-associated cytokines, IL-4, IL-5, and IL-13, from tissue-resident innate-immune cells, especially ILCs and MCs.

"Toll"-erance in the skin.

Interactions between potentially pathogenic commensal bacteria and cutaneous immunity are poorly understood. In this issue of Immunity, Skabytska et al. (2014) show that S.

Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses.

Background: Efficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after FcεRI cross-linking by antigen-IgE complexes (FcεRI-activated mast cells [FcεRI-MCs]).

Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12.

Substance-P and hemokinin-1 are proinflammatory neuropeptides with potential to promote type 1 immunity through agonistic binding to neurokinin-1 receptor (NK1R). Dendritic cells (DCs) are professional antigen-presenting cells that initiate and regulate the outcome of innate and adaptive immune responses. Immunostimulatory DCs are highly desired for the development of positive immunization techniques.

Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO.

Hepatic stellate cells (HSCs) are critical for hepatic wound repair and tissue remodeling. They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver. The functional relationship between HSCs and the professional migratory APCs in the liver, that is, dendritic cells (DCs), has not been evaluated.

Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver.

Obesity-associated increases in adipose tissue (AT) CD11c(+) cells suggest that dendritic cells (DC), which are involved in the tissue recruitment and activation of macrophages, may play a role in determining AT and liver immunophenotype in obesity. This study addressed this hypothesis. With the use of flow cytometry, electron microscopy, and loss-and-gain of function approaches, the contribution of DC to the pattern of immune cell alterations and recruitment in obesity was assessed.

IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) are highly specialized APCs that, in addition to their well-recognized role in anti-viral immunity, also regulate immune responses. Liver-resident pDCs are considerably less immunostimulatory than those from secondary lymphoid tissues and are equipped to promote immune tolerance/regulation through various mechanisms. IL-27 is an IL-12 family cytokine that regulates the function of both APCs and T cells, although little is known about its role in pDC immunobiology.

Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: role of endotoxin and implications for allograft tolerance.

Hepatic stellate cells (HSCs) may play an important role in hepatic immune regulation by producing numerous cytokines/chemokines and expressing Ag-presenting and T cell coregulatory molecules. Due to disruption of the endothelial barrier during cold-ischemic storage and reperfusion of liver grafts, HSCs can interact directly with cells of the immune system. Endotoxin (LPS), levels of which increase in liver diseases and transplantation, stimulates the synthesis of many mediators by HSCs.

The STATus of PD-L1 (B7-H1) on tolerogenic APCs.

Expression by DCs of co-inhibitory molecules such as programmed death ligand-1 (PD-L1/B7-H1/CD274), a member of the B7 superfamily, is crucial for the downregulation of T-cell responses and the maintenance of immune homeostasis. Exposure of immature DCs to danger-associated molecular patterns (DAMPS) or pathogen-associated molecular patterns (PAMPs) generally results in their maturation and acquisition of immunostimulatory function. However, exposure of DCs to TLR ligands early during their differentiation can inhibit further differentiation and confer tolerogenic properties on these APCs.