ABSTRACT
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/pathologySubject(s)
CD4-Positive T-Lymphocytes/metabolism , Ikaros Transcription Factor/metabolism , Mycosis Fungoides/immunology , Receptors, Immunologic/metabolism , Sezary Syndrome/immunology , Skin Neoplasms/immunology , Biomarkers, Tumor/metabolism , CD4-Positive T-Lymphocytes/immunology , Gene Expression Profiling , Humans , Ikaros Transcription Factor/immunology , Lymphocyte Activation/immunology , Microarray Analysis , Mycosis Fungoides/blood , Mycosis Fungoides/pathology , Neoplasm Staging , RNA, Messenger/metabolism , Receptors, Immunologic/immunology , Sezary Syndrome/blood , Sezary Syndrome/pathology , Skin/pathology , Skin Neoplasms/blood , Skin Neoplasms/pathology , Tumor BurdenABSTRACT
Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.
