Sensory neurons: An integrated component of innate immunity.

The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate 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. In this review article, we will explore emerging research describing neuronal effector functions on skin immune cells in mouse models of atopic and contact dermatitis. We will also discuss the contributions of both specific neuronal subsets and secreted immune factors to itch induction and the associated inflammatory processes. Finally, we will explore how treatment strategies have emerged around these findings and discuss the relationship between scratching and dermatitis.

Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells.

The cytokine interleukin-23 (IL-23) is critical for development and maintenance of autoimmune inflammation in nonlymphoid tissues; however, the mechanism through which IL-23 supports tissue-specific immunity remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from Candida albicans skin infection, and tissue-resident memory (TRM) cell-mediated protection from C. albicans reinfection required IL-23. Administration of anti-IL-23 receptor antibody to mice after resolution of primary C. albicans infection resulted in loss of CD69+ CD103+ tissue-resident memory T helper 17 (TRM17) cells from skin, and clinical anti-IL-23 therapy depleted TRM17 cells from skin of patients with psoriasis. IL-23 receptor blockade impaired TRM17 cell proliferation but did not affect apoptosis susceptibility or tissue egress. IL-23 produced by CD301b+ myeloid cells was required for TRM17 maintenance in skin after C. albicans infection, and CD301b+ cells were necessary for TRM17 expansion during the development of imiquimod dermatitis. This study demonstrates that locally produced IL-23 promotes in situ proliferation of cutaneous TRM17 cells to support their longevity and function and provides mechanistic insight into the durable efficacy of IL-23 blockade in the treatment of psoriasis.

TGFß activating integrins ß6 and ß8 are dysregulated in inflammatory skin disease and cutaneous melanoma.

BACKGROUND: Integrins avß6 and avß8 are expressed by keratinocytes and transactivate latent TGFß. In a murine model, integrin mediated activation of TGFß has been shown to be critical in maintaining skin homeostasis, specifically playing roles in epidermal retention of Langerhans cells and resident memory cells T cells (Trm). OBJECTIVE: We examine expression of Integrins ß6 and ß8 in human skin, inflammatory skin disease, benign nevi, and melanoma and hypothesize that integrin expression is dysregulated in disease. METHODS: Using immunohistochemistry, we stained tissue from normal human skin (n = 8), psoriasis (n = 6), atopic dermatitis (n = 6), lichen planus (n = 5), benign nevi (n = 24), and melanoma (n = 25) with anti-integrin ß6 and anti-integrin ß8 to survey expression pattern. We also performed a retrospective chart review in the melanoma cohort to examine if integrin ß6 and ß8 expression was associated with increased Breslow depth and worse prognostic staging. RESULTS: Here, we show that human keratinocytes express integrins ß6 and ß8, similar to murine keratinocytes. We also found that inflammatory skin conditions have increased Integrin ß6, but not Integrin ß8 expression. Furthermore, we identified that melanomas have greatly increased expression of integrin ß8 compared to nevi. Additionally, high expression of integrin ß8 was correlated with greater Breslow depth at diagnosis and with worse prognostic staging. CONCLUSION: These findings demonstrate that like murine keratinocytes, human keratinocytes express integrin ß6 and ß8 under steady state conditions. Moreover, altered integrin expression may participate in the development or maintenance of cutaneous inflammation as well as tumor immune evasion.

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. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated. OBJECTIVE: We sought to develop an Ag-specific immunosuppressive approach to treat CD by skin codelivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA). METHODS: In vivo mouse models of contact hypersensitivity and ex vivo models of human skin were used to delineate the effects and mechanisms of NK1R signaling and the immunosuppressive effects of the contact sensitizer NK1R antagonist MNA in CD. RESULTS: We demonstrated in mice that CD requires NK1R signaling by substance P and hemokinin 1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells, prevented CD. Skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells, and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner. CONCLUSIONS: Immunoregulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD are caused by type 1 immunity.

Inflammatory thoughts can upset your guts.

Peripheral neurons and immune cells interact to modulate inflammation, but whether the brain can control this process is unknown. In a recent issue of Cell, Koren et al. (2021) show that peripheral inflammation is encoded in the insular cortex and that later re-activation of these neurons triggers inflammation.

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. In this review, we will focus on the reciprocal interactions between cutaneous sensory neurons and MCs and the importance of this cross-talk in skin diseases.

TNF-α and IL-1ß Do Not Induce Langerhans Cell Migration by Inhibiting TGFß Activation.

In the skin, Langerhans cells (LCs) require autocrine latent TGFß that is transactivated by the integrins ανß6 and ανß8 expressed by keratinocytes (KCs) for long-term epidermal retention. Selective expression of a ligand-independent, constitutively active form of TGFßR1 inhibits LC migration during homeostasis and in response to UVB exposure. In this study, we found that LC migration in response to inflammatory stimuli was also inhibited by ligand-independent TGFßR1 signaling. Contrary to UVB stimulation, which reduced KC expression of ανß6, in vitro and in vivo exposure to TNF-α or IL-1ß increased ανß6 transcript and protein expression by KCs. This resulted in increased KC-mediated transactivation of latent TGFß. Expression of ανß8 was largely unchanged. These findings show that ligand-independent TGFßR1 signaling in LCs can overcome inflammatory migration stimuli, but reduced KC-mediated transactivation of latent TGFß by KCs may only drive LC migration during homeostasis and in response to UV stimulation.

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. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.

Gut Helicobacter presentation by multiple dendritic cell subsets enables context-specific regulatory T cell generation.

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103+ gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacter-specific T cell receptor (TCR) transgenic mouse lines, we found that both CD103+ and CD103- migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103+ migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103- DCs. By contrast, activation in a Th1-promoting niche in vivo blocked Helicobacter-specific pTreg generation. Thus, these data suggest a model where DC-mediated effector T cell differentiation is 'dominant', necessitating that all DC subsets presenting antigen are permissive for pTreg cell induction to maintain gut tolerance.

Dual function of Langerhans cells in skin TSLP-promoted TFH differentiation in mouse atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is among the most common chronic inflammatory skin diseases, usually occurring early in life, and often preceding other atopic diseases such as asthma. TH2 has been believed to play a crucial role in cellular and humoral response in AD, but accumulating evidence has shown that follicular helper T cell (TFH), a critical player in humoral immunity, is associated with disease severity and plays an important role in AD pathogenesis. OBJECTIVES: This study aimed at investigating how TFHs are generated during the pathogenesis of AD, particularly what is the role of keratinocyte-derived cytokine TSLP and Langerhans cells (LCs). METHODS: Two experimental AD mouse models were employed: (1) triggered by the overproduction of TSLP through topical application of MC903, and (2) induced by epicutaneous allergen ovalbumin (OVA) sensitization. RESULTS: This study demonstrated that the development of TFHs and germinal center (GC) response were crucially dependent on TSLP in both the MC903 model and the OVA sensitization model. Moreover, we found that LCs promoted TFH differentiation and GC response in the MC903 model, and the depletion of Langerin+ dendritic cells (DCs) or selective depletion of LCs diminished the TFH/GC response. By contrast, in the model with OVA sensitization, LCs inhibited TFH/GC response and suppressed TH2 skin inflammation and the subsequent asthma. Transcriptomic analysis of Langerin+ and Langerin- migratory DCs revealed that Langerin+ DCs became activated in the MC903 model, whereas these cells remained inactivated in OVA sensitization model. CONCLUSIONS: Together, these studies revealed a dual functionality of LCs in TSLP-promoted TFH and TH2 differentiation in AD pathogenesis.

Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures.

Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the United States population. This guideline addresses important clinical questions that arise in psoriasis management and care and provides recommendations based on the available evidence. The treatment of psoriasis with topical agents and with alternative medicine will be reviewed, emphasizing treatment recommendations and the role of dermatologists in monitoring and educating patients regarding benefits as well as risks that may be associated. This guideline will also address the severity assessment methods of psoriasis in adults.

Competition for Active TGFß Cytokine Allows for Selective Retention of Antigen-Specific Tissue- Resident Memory T Cells in the Epidermal Niche.

Following antigen-driven expansion in lymph node, transforming growth factor-ß (TGFß) is required for differentiation of skin-recruited CD8+ T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFß -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFß was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFßR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFß represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche.

Single-Cell Profiling Reveals Divergent, Globally Patterned Immune Responses in Murine Skin Inflammation.

Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA sequencing, after inducing inflammation using imiquimod and oxazolone dermatitis models. We identify 13 CD45+ subpopulations, which broadly represent most functionally characterized immune cell types. Oxazolone pervasively upregulates Jak2/Stat3 expression across T cells and antigen-presenting cells (APCs). Oxazolone also induces Il4/Il13 expression in newly infiltrating basophils, and Il4ra and Ccl24, most prominently in APCs. In contrast, imiquimod broadly upregulates Il17/Il22 and Ccl4/Ccl5. A comparative analysis of single-cell inflammatory transcriptional responses reveals that APC response to oxazolone is tightly restricted by cell identity, whereas imiquimod enforces shared programs on multiple APC populations in parallel. These global molecular patterns not only contrast immune responses on a systems level but also suggest that the mechanisms of new sources of inflammation can eventually be deduced by comparison to known signatures.

An IL-17F.S65L Knock-In Mouse Reveals Similarities and Differences in IL-17F Function in Oral Candidiasis: A New Tool to Understand IL-17F.

Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans IL-17R signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F, and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this "experiment of nature" by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9. Unlike Il17f-/- mice that are resistant to OPC, Il17fS65L/S65L mice showed increased oral fungal burdens similar to Il17a -/- mice. In contrast to humans, however, disease was only evident in homozygous, not heterozygous, mutant mice. The mutation was linked to modestly impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in oral antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi. Moreover, because these mice do not phenocopy Il17f-/- mice, they may provide a valuable tool to interrogate IL-17F and IL-17AF function in vivo in other settings.

Oral epithelial IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral mucosal candidiasis.

Oropharyngeal candidiasis (OPC; thrush) is an opportunistic infection caused by the commensal fungus Candida albicans Interleukin-17 (IL-17) and IL-22 are cytokines produced by type 17 lymphocytes. Both cytokines mediate antifungal immunity yet activate quite distinct downstream signaling pathways. While much is now understood about how IL-17 promotes immunity in OPC, the activities of IL-22 are far less well delineated. We show that, despite having similar requirements for induction from type 17 cells, IL-22 and IL-17 function nonredundantly during OPC. We find that the IL-22 and IL-17 receptors are required in anatomically distinct locations within the oral mucosa; loss of IL-22RA1 or signal transducer and activator of transcription 3 (STAT3) in the oral basal epithelial layer (BEL) causes susceptibility to OPC, whereas IL-17RA is needed in the suprabasal epithelial layer (SEL). Transcriptional profiling of the tongue linked IL-22/STAT3 not only to oral epithelial cell proliferation and survival but also, unexpectedly, to driving an IL-17-specific gene signature. We show that IL-22 mediates regenerative signals on the BEL that replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to respond to IL-17 and thus to mediate antifungal events. Consequently, IL-22 signaling in BEL "licenses" IL-17 signaling in the oral mucosa, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis.

Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies.

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 2% of the world's population. In this guideline, we focus the discussion on systemic, nonbiologic medications for the treatment of this disease. We provide detailed discussion of efficacy and safety for the most commonly used medications, including methotrexate, cyclosporine, and acitretin, and provide recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally, we discuss newer therapies, including tofacitinib and apremilast, and briefly touch on a number of other medications, including fumaric acid esters (used outside the United States) and therapies that are no longer widely used for the treatment of psoriasis (ie, hydroxyurea, leflunomide, mycophenolate mofetil, thioguanine, and tacrolimus).

Neuronal Regulation of Cutaneous Immunity.

The skin is innervated by numerous sensory afferent neurons that respond to a diverse array of stimuli ranging from gentle touch to noxious pain. Various features of the immune system-pathogen recognition, secretion of soluble mediators-are shared with the nervous system. This has led to the recognition that neurons share some functions with innate immune cells and have the capacity to recognize pathogens and participate in innate immune responses. Neuroimmune interactions are bidirectional. Soluble mediators from immune cells activate neurons and soluble mediators from neurons can activate immune cells. In this review, we will focus on the interplay between neurons and innate immunity in the skin in the context of host defense and inflammation.

Migration and Function of Memory CD8+ T Cells in Skin.

CD8+ memory T cells provide anamnestic host defense against intracellular pathogens and cancer immunosurveillance but are also pathogenic in some autoimmune diseases. In mouse skin, there are two unique subsets of CD8+ memory T cells, resident memory cells that reside long-term in steady state skin and recirculating memory cells that are transient. They have distinct mechanisms of recruitment, development, and maintenance in response to skin-derived signals. In this review, we will focus on these mechanisms and the functional relationship of these two types of CD8+ memory cells with host defense and disease.