Janus kinases such as abuxitinib（jak）1 inhibitorClinical trials are ongoing for atopic dermatitis (AD) and for asthma, but in fact, the mechanisms associated with major adverse events (including cardiovascular events, cancer, and opportunistic infections) with JAK inhibitors remain unclear. For the first time, the study revealed the role of neuronal JAK1 in regulating neuropeptide expression and neuroinflammation, clarifying the tissue specificity of the system, the importance of JAK signaling, and the potential utility of JAK inhibitors across the disease spectrum. JAK1 signaling is a major target of AD and pruritusThe sensory neuronal innate signaling of JAK1 exerts an immunomodulatory role in the lungsThe results of this study contribute to a deeper understanding of the biological significance of JAK signaling and the prospects for its use in the medical field.
Basics:
JAKs are a class of kinases that belong to the tyrosine kinase family, which includes four members: JAK1, JAK2, JAK3, and TYK2.
Abstract Figure: JAK1 signaling promotes inflammation and is the main target of AD and pruritus, and the JAK1 GOF mutation promotes spontaneous inflammation in mice, but the expression of JAK1 GOF mutation in vagus sensory neurons promotes lung immune homeostasis, and the neuronal JAK1-CGRPB axis can inhibit ILC2 response and allergic lung inflammation. This study highlights the immunomodulatory role of JAK1 sensory neuronal innate signaling in the lungs.
Human JAK1 GOF mutations are associated with AD and asthma in patients and promote spontaneous AD-like disease in mice. In 2017, the first patients carrying germline JAK1 GOF mutations were identified as replacing alanine at position 634 (A634D) within the inhibitory pseudokinase domain of the JAK1 protein with aspartic acid. These patients present with a variety of allergic diseases, including AD, asthma, and severe eosinophilia. Interestingly, the human JAK1 GOF mutation promotes spontaneous allergic inflammation, but not in the lungs (Figure 1).
The investigators established JAK1 genotype chimeric mice (WT WT and WT JAK1GOF) with hematopoietic and stromal cell components, and administered JAK1GOF and control mice intranasal** with the allergen Alternaria alternata, an asthma associated fungus. Through in vivo immunohistochemistry, RNA-Seq and other techniques**The effect of stromal JAK1GOF on allergen-induced lung inflammation was investigated, and it was determined that the intrinsic expression of JAK1GOF had a protective effect on allergic lung inflammation(Figure 2).
The investigators hypothesize that sensory neurons in the lungs may play a role in inhibiting inflammation. **Innervated almost exclusively by sensory neurons produced by the dorsal root ganglia (DRG), whereas the lung is innervated primarily by sensory afferents produced by VG, which also has a small amount of innervation. A large number of TRPV1 receptors are distributed on DRG neurons, which is a non-selective cation channel that induces neuronal inward currents upon activation and plays an important role in the perception, transmission, and regulation of nociceptive stimuliThe study found that allergic lung inflammation was exacerbated by chemical denervation of TRPV1+ sensory neurons, supporting the signaling of sensory neurons to inhibit allergic lung inflammation(Figure 3).
Whether JAK1 is expressed in the vagus ganglia (VG) is unknown. DRGs are known to express the typical nociceptive marker n**18. The researchers analyzed the scrna-seq dataset of VG and found that most of the n**18+ sensory neurons co-express JAK1, it is believed that JAK1, which is intrinsic to sensory neurons, regulates lung inflammation and neuropeptide levels, and that disruption of JAK1 intrinsic to sensory neurons exacerbates allergic lung inflammation and alters neuropeptide expression levels, thereforeSensory neurons of DRGs express JAK1 to mediate key functions such as pruritus(Figure 4).
Based on the above sequencing results, the researchers screened a variety of neuropeptides associated with neuroinflammation and found thatExpression of JAK1 is required for proper expression of Calcb, which encodes the neuropeptide calcitonin gene-related peptide B(cgrpb)Group 2 innate lymphocytes (ILC2), which are known to be involved in type 2 inflammation, are important drivers of allergic lung inflammation, and neuropeptides have been shown to inhibit ILC2 response and lung inflammation. The investigators sorted and purified lung ILC2 from WT C57BL6 mice and stimulated it in vitro using the cytokine IL-33 in combination with CGRPB or SP to determine whether CGRPB inhibits ILC2 function. The hypothesis was verified through a series of ELISA, immunohistochemistry and other techniques, and the conclusions were drawn:CGRPB can inhibit type 2 cytokine production by ILC2 in the lungs and allergic lung inflammation(Figure 5).
Next, the investigators hypothesized that specific delivery of JAK1 GOF to innervating neurons in the lungs would inhibit allergic lung inflammation. Retrograde adeno-associated virus (A**) and human JAK1 GOF variants co-expressing CRE recombinase were introduced into ROSA26STOPFLOX-TDTOMATO mice, and they were challenged for alternaria allergens in the airways. It is clear that allergic lung inflammation can be prevented by retrograde viral delivery and insertion of human JAK1 GOF into sensory neuronsExpression of human JAK1GOF in pulmonary sensory neurons can inhibit allergic inflammation. (Figure 6).
This study reveals a previously unrecognized role of neuronal JAK1 in regulating neuropeptide expression and neuroinflammation. The study highlights the importance of tissue-specific JAK signaling across mammalian systems and the potential utility of JAK inhibitors across the disease lineage.
Corresponding author
brian s.Kim is now a professor at the Icahn School of Medicine at Mount Sinai. His team was the first to discover IL-4 receptor signaling on sensory neurons and the first to identify JAK1 signaling in sensory neurons. In 2021, Brian SKim has been published in Cell Magazine**: