JAK1 is an important protein in the body that supports cell-to-cell communication and the regulation of the immune system. Control of JAK1 activity is essential for certain cancers and diseases such as rheumatoid arthritis. Currently, the US FDA has approved multiple JAK1 inhibitors for eczema**, but none have been used for asthma**, and multiple inhaled JAK1 inhibitors have failed in clinical trials. Therefore, we need to better understand the tissue-specific role of JAK signaling in various organs.
Type II cytokines rely primarily on JAK1 signaling to promote allergic inflammation. However, the understanding of JAK inhibition comes primarily from the hematopoietic system. Little is known about the role of JAK1 signaling in stromal cells such as epithelial cells and fibroblasts. In order to better ** allergic diseases, an in-depth understanding of the specific role of JAK1 signaling in tissues and cells is needed.
Recently, researchers at the Icahn School of Medicine at Mount Sinai revealed a previously undiscovered role of JAK1 in vagus sensory neurons in a mouse model. The findings, published in the journal Cell on January 4, 2024, are expected to help optimize the best JAK inhibitors in the future to enhance precision medicine.
In this study, the researchers used multiple mouse models, including C57BL6 wild-type mice, adaptive lymphocyte-deficient RAG1- mice, and others. Allergic lung inflammation was induced by nasal injection of Alternaria and pathological changes in the lungs were assessed by histopathology. They also analyzed the expression of multiple neuropeptides in vagus neurons and how they are affected by JAK1.
After constructing JAK1GOF mice and conducting airway allergen challenge experiments, the researchers found that JAK1GOF mice had an inhibitory effect on allergen-induced lung inflammation. Further experiments proved that the inflammatory response of the lungs of JAK1GOF mice to allergen stimulation was relatively weak, suggesting that the lungs have some resistance to JAK1-mediated inflammation.
The researchers also found that JAK1 in sensory neurons has a regulatory effect on lung inflammation and neuropeptide levels. It has been experimentally demonstrated that the expression of JAK1 in vagus sensory neurons is essential for allergic inflammation of the lungs. In addition, the regulation of JAK1 in sensory neurons affects the expression of a variety of neuropeptides, including CGRP.
Finally, the researchers successfully suppressed allergic lung inflammation by inserting human JAK1 GOF into mouse sensory neurons. This finding suggests that the regulation of neuropeptides by JAK1 in sensory neurons may contribute to the maintenance of immune homeostasis in the lungs.
Overall, this study reveals the immunomodulatory role of JAK1 in the sensory nervous system, providing a new perspective for the future** allergic diseases. Sensory neurons may become an important factor in regulating immune homeostasis through JAK1 signaling, which opens up a new research direction for neuroimmune diseases.