The human body intricately responds to various stimuli, encompassing living tissue and an array of living and non-living factors, including bacteria, viruses, and toxic chemicals. Inflammation, a pivotal facet of the body’s defense mechanism against injury or infection, constitutes the innate response of our immune system to any perceived threat. In the face of an irritant, the body deploys inflammatory cells and cytokines to safeguard itself, initiating the healing process. Remarkably, in the context of ongoing scientific research targeting the treatment of asthma, an escalating atopic disorder, a noteworthy revelation has surfaced: Sensory neurons play a significant role in maintaining immune homeostasis within the lung.
Janus Kinase (JAK) inhibitors, operating by transmitting signals through cytokine receptors activated in lymphocytes, macrophages, endothelium, epithelium, and connective tissues, present a novel therapeutic avenue for addressing atopic diseases associated with inflammation and immunity. These inhibitors exert their effect by blocking signal transducer transcription. The exploration of JAK inhibitors, with their as yet unidentified tissue and cell-specific pathological impacts, is essential. Notably, JAK1-dependent type 2 cytokines are implicated in triggering allergic inflammation, leading to the development of atopic dermatitis (AD) and asthma in individuals with gain-of-function (JAK1 GoF) variants. This is demonstrated through the induction of atopic dermatitis and asthma in mice injected with the JAK1 GoF mutation, providing valuable insights into the potential applications of JAK inhibitors.
Tamari and his colleagues injected the JAK1 GoF mutation into mice to learn the various mechanisms and pathological effects of JAK1 inhibitors. As expected, mice exhibited AD-like inflammation as in humans, but no lung pathology was evident at a steady state. However, the spheroid JAK1GoF mouse exhibited increased allergic lung inflammation in response to the classical allergen Alternaria alternata. Tissue-restricted JAK1GoF expression enabled mice to resist allergic lung inflammation. By screening the neuropeptides that cause this condition, it was discovered that CGRPβ associated with the calcitonin gene suppresses lung inflammation and that JAK1 expression is required for its coding. In both results, the localization of JAK 1 GOF to sensory neurons supported the immune balance in the lung.
Human genes and mouse were used in the experimental process. In treating lung inflammation in mice injected with JAK1 inhibitors, the fungus Alternaria alternata extract, papain, and neuropeptides were used and upadacitinib and tamoxifen were used. RNA-seq alignment and quality control were used to obtain the gene sequence of lung tissue, and single-cell RNA-seq analysis of JG/NG was used to determine the ILC2 response of neuropeptides. Various software, flow charts, and graphics were used to enter the data of this valuable research.
It is known that JAK1 inflammatory resistance is observed in the lungs, it was hypothesized that JAK1 activation in the lung stroma combats allergy. When we looked at JAK1 mice and control mice, they exhibited reduced lung pathology as evidenced by reduced perivascular inflammatory leaks. In addition, it was concluded that asthma and inflammation in the lung tissue of the mouse were significantly suppressed. That is, JAK1GoF stromal expression confers resistance to lung inflammation. Because of these inferences, the hypothesis was developed that JAK1 expression within sensory neurons is required for immune homeostasis in the lung. Using mice lacking JAK1 in their neurons, pathological findings in inflammation showed that JAK1 signaling in sensory neurons regulates allergic inflammation.
In spite of research that has shown that JAK1 signaling is required in allergic lung inflammation, it is still unclear whether this function is affected by JAK1 selective inhibitors in humans. To find out how this is reflected in humans, pluripotent stem cells will be effective on human sensory neurons in the future.
Author: Gülmiray Aydın
Editor: Elif Duymaz
Reference: Tamari, M., Del Bel, K. L., Ver Heul, A. M., Zamidar, L., Orimo, K., Hoshi, M., Trier, A. M., Yano, H., Yang, T. L., Biggs, C. M., Motomura, K., Shibuya, R., Yu, C. D., Xie, Z., Iriki, H., Wang, Z., Auyeung, K., Damle, G., Demircioglu, D., Gregory, J. K., … Kim, B. S. (2024). Sensory neurons promote immune homeostasis in the lung. Cell, 187(1), 44–61.e17. https://doi.org/10.1016/j.cell.2023.11.027
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