Targeted therapy against Interleukin-9 Receptor (IL-9R) has achieved a major breakthrough in the field of autoimmunity. AnaptysBio, a US-based company, announced the success of its Phase II study of the anti-IL-9R monoclonal antibody Imsidolimab for the treatment of moderate-to-severe Ulcerative Colitis (UC). This study suggests that blocking IL-9R not only directly inhibits inflammation but may also function by repairing intestinal barrier integrity.
 

As a key hub in cytokine signaling pathways, IL-9R plays complex roles in immune-related diseases. Let's explore this further.
 

IL-9R is a type I transmembrane protein that forms a heterodimeric receptor complex with the common gamma chain (γc), consisting of the ligand-specific α chain (IL-9Rα) and the signal-transducing γ chain (γc). It is primarily expressed on T cells, B cells, mast cells, neutrophils, and epithelial cells. Its core signaling pathway is the JAK-STAT pathway: when IL-9 binds to IL-9Rα, it recruits and activates JAK1 associated with IL-9Rα and JAK3 associated with γc, subsequently phosphorylating tyrosine residues in the intracellular domain of IL-9Rα, providing docking sites for STAT proteins (mainly STAT1, STAT3, STAT5). Phosphorylated STATs form homo- or heterodimers that translocate to the nucleus to initiate transcription of specific genes (such as BCL-2 family members, cyclins, and inflammatory factors). Additionally, IL-9R can activate the PI3K-Akt pathway via Insulin Receptor Substrate (IRS) proteins to promote cell survival, and weakly activate the MAPK pathway to influence cell proliferation.
 

 

(Image placeholder: An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis)

I.  Asthma and Allergy: IL-9R-Mediated Inflammatory Cascade Amplification Mechanism
 

In allergic asthma, IL-9R plays a central role as an "inflammatory amplifier," driving the cascade from initial sensitization to chronic inflammation. The mechanism begins in mediastinal lymph nodes, where dendritic cells present inhaled allergens and, under the influence of IL-4 and TGF-β, drive the differentiation of naive CD4+ T cells into IL-9-secreting Th9 cells. IL-9, as a key signaling molecule, acts on various IL-9R-expressing target cells, forming a vicious cycle: in mast cells, IL-9R signaling via the STAT3 pathway promotes the migration, proliferation, and differentiation of mast cell/basophil precursors in the bone marrow, while also enhancing FcεRI-mediated degranulation, releasing mediators such as histamine and tryptase, triggering acute bronchospasm. In airway epithelial cells, IL-9R activation induces the production of mucins MUC5AC and MUC5B, leading to excessive airway mucus secretion and plugging; it also upregulates alarmins like calprotectin, continuously amplifying Th2-type inflammatory responses. In airway smooth muscle, recent studies have found that IL-9R activation enhances sensitivity to histamine and acetylcholine, directly causing airway hyperresponsiveness. Gene knockout studies confirm that IL-9R deficiency significantly reduces airway inflammation, hyperresponsiveness, and mucus hypersecretion in models.
 

(Image placeholder: Interleukin 9 and its Receptor: An Overview of Structure and Function)

II.  Autoimmune Diseases: IL-9R-Driven Tissue Destruction and Immune Imbalance Mechanisms
 

IL-9R signaling drives autoimmune pathological processes through cell-specific mechanisms. In Multiple Sclerosis (MS), IL-9R activation on oligodendrocytes via the STAT1 pathway induces endoplasmic reticulum stress and inhibits remyelination, directly leading to demyelinating lesions. In Rheumatoid Arthritis (RA), IL-9R on synovial neutrophils significantly prolongs cell lifespan via the STAT5 pathway and stimulates the release of MMP-9 and Neutrophil Extracellular Traps (NETs), exacerbating bone and cartilage erosion. Breakthrough research in Ulcerative Colitis (UC) found that targeting IL-9R can simultaneously repair the intestinal barrier composed of tight junction proteins in intestinal epithelial cells and induce apoptosis of pathological neutrophils in the lamina propria, achieving dual therapeutic effects.
 

III. Tumor Immunity: Dual-Fate Mechanism of IL-9R Signaling in the Tumor Microenvironment
 

The role of IL-9R in tumors exhibits a cell-dependent "dual nature." In hematological malignancies such as Chronic Lymphocytic Leukemia (CLL), activation of IL-9R on tumor cells upregulates anti-apoptotic proteins like BCL-2 and MCL-1 via STAT3/STAT5 pathways, directly promoting tumor survival and proliferation. Conversely, in solid tumors like melanoma, IL-9R signaling on dendritic cells (DCs) has been shown to enhance antigen presentation function and secrete CCL20 to recruit CCR6+ cytotoxic T cells, thereby stimulating anti-tumor immunity.
 

(Image placeholder: Interleukin (IL)-9 Supports the Tumor-Promoting Environment of Chronic Lymphocytic Leukemia)

Mouse Models
 

IL-9R KO Mice: In asthma and colitis models, airway and intestinal inflammation, mucus secretion, and tissue damage are significantly reduced.
 

IL-9R Humanized Mice: Simulate IL-9R-related immune responses and pathological processes in human diseases, used to evaluate the pharmacodynamic properties of humanized antibody drugs and study the role of IL-9R in human disease mechanisms.
 

MingCeler Biotech Facilitates Mechanism Research and Drug Development
 

Gene therapy offers hope for common diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech can customize various IL9R-related mouse models according to client needs, such as IL-9R KO mice and IL-9R humanized mice. We welcome inquiries.

 

References:

[1] https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL9R

[2] Chakraborty, S.; Kubatzky, K.F.; Mitra, D.K. An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis. Int. J. Mol. Sci. 2019, 20, 2113.

[3] Interleukin-9 promotes mast cell progenitor proliferation and CCR2-dependent mast cell migration in allergic airway inflammation. Pajulas, Abigail et al. Mucosal Immunology, Volume 16, Issue 4, 432 – 445.

[4] Lu Y, Hong B, Li H, Zheng Y, Zhang M, Wang S, Qian J, Yi Q. Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2265-70. doi: 10.1073/pnas.1317431111. Epub 2014 Jan 27. PMID: 24469818; PMCID: PMC3926063.

[5] Patrussi, L.; Capitani, N.; Baldari, C.T. Interleukin (IL)-9 Supports the Tumor-Promoting Environment of Chronic Lymphocytic Leukemia. Cancers 2021, 13, 6301.

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