ABSTRACT
Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.
Subject(s)
Basophils/pathology , Neurons/pathology , Pruritus/pathology , Acute Disease , Allergens/immunology , Animals , Chronic Disease , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Disease Models, Animal , Histamine/metabolism , Humans , Immunoglobulin E/immunology , Inflammation/pathology , Leukotrienes/metabolism , Mast Cells/immunology , Mice, Inbred C57BL , Phenotype , Pruritus/immunology , TRPA1 Cation Channel/metabolism , TRPV Cation Channels/metabolismABSTRACT
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
Subject(s)
Pruritus/immunology , Sensory Receptor Cells/immunology , Sensory Receptor Cells/metabolism , Signal Transduction , Skin Diseases/immunology , Animals , Ganglia, Spinal , Humans , Interleukin-13/immunology , Interleukin-4/immunology , Janus Kinase 1/metabolism , Mice , Mice, Inbred C57BL , Pruritus/metabolism , Skin Diseases/pathologyABSTRACT
This JAMA Clinical Guidelines Synopsis summarizes the American Academy of Dermatology's 2023 guidelines for topical-therapy management of adults with atopic dermatitis.
Subject(s)
Dermatitis, Atopic , Dermatologic Agents , Humans , Administration, Topical , Calcineurin Inhibitors , Dermatitis, Atopic/drug therapy , Dermatologic Agents/administration & dosage , Dermatologic Agents/therapeutic useABSTRACT
A 50-year-old man with a history of alcoholic cirrhosis status post liver transplant about 3 months prior to consultation presented with abnor-mal appearing fingernails for the past month. He had noted discoloration of his fingernails, which was initially dark pink and asymptomatic. He denied trauma or any new contactants to the nails.
Subject(s)
Liver Cirrhosis, Alcoholic , Liver Transplantation , Humans , Liver Transplantation/adverse effects , Male , Middle Aged , Liver Cirrhosis, Alcoholic/complications , Liver Cirrhosis, Alcoholic/surgery , Nail Diseases/pathology , Nail Diseases/etiology , Nail Diseases/diagnosis , Nail Diseases/surgerySubject(s)
Immunosenescence/immunology , Pruritus/immunology , Pruritus/pathology , Th2 Cells/immunology , Aged , Antipruritics/therapeutic use , Biopsy, Needle , Chronic Disease , Female , Humans , Immunohistochemistry , Immunosenescence/physiology , Male , Middle Aged , Prognosis , Pruritus/drug therapy , Risk Assessment , Sampling Studies , Severity of Illness IndexABSTRACT
Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. Current treatments involve either broad or targeted immunosuppression strategies. However, enhancing the immune system to control disease remains untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that both has diagnostic value and improves with therapy. Multidimensional protein and RNA profiling revealed subset-level changes associated with enhanced NK cell death. Murine NK cell deficiency was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role in this context. On the basis of these findings, we used an NK cell-boosting interleukin-15 (IL-15) superagonist and observed marked improvement in AD-like disease in mice. These findings reveal a previously unrecognized application of IL-15 superagonism, currently in development for cancer immunotherapy, as an immunotherapeutic strategy for AD.
Subject(s)
Dermatitis, Atopic , GATA2 Deficiency , Animals , Dermatitis, Atopic/therapy , Disease Models, Animal , Humans , Immunotherapy , Killer Cells, Natural , MiceSubject(s)
Arthralgia , Fever , Urticaria , Humans , Arthralgia/etiology , Fever/etiology , Urticaria/diagnosis , Urticaria/etiology , Exanthema/etiology , Male , Female , Diagnosis, DifferentialABSTRACT
We examined the psychology of "instigators," people who surround an unethical act and influence the wrongdoer (the "actor") without directly committing the act themselves. In four studies, we found that instigators of unethical acts underestimated their influence over actors. In Studies 1 and 2, university students enlisted other students to commit a "white lie" (Study 1) or commit a small act of vandalism (Study 2) after making predictions about how easy it would be to get their fellow students to do so. In Studies 3 and 4, online samples of participants responded to hypothetical vignettes, for example, about buying children alcohol and taking office supplies home for personal use. In all four studies, instigators failed to recognize the social pressure they levied on actors through simple unethical suggestions, that is, the discomfort actors would experience by making a decision that was inconsistent with the instigator's suggestion.