The immune system uses chemical messengers called cytokines to coordinate its responses and regulate inflammation. Interleukin-36 (IL-36) is a cytokine in the interleukin-1 (IL-1) family, playing a role in both normal immune function and various inflammatory processes.
Understanding IL-36
IL-36 is a cytokine primarily produced by cells including keratinocytes, epithelial cells, and immune cells such as monocytes, macrophages, and T cells. It exists in three agonist forms: IL-36 alpha (IL-36α), IL-36 beta (IL-36β), and IL-36 gamma (IL-36γ), which activate the IL-36 receptor. An antagonist form, IL-36 receptor antagonist (IL-36Ra), binds to the same receptor but blocks its activation, inhibiting inflammatory signals. The IL-36 receptor (IL-36R) is found on target cell surfaces, allowing IL-36 to transmit signals.
IL-36 cytokines are initially inactive and require N-terminal cleavage by enzymes to become fully active. Once activated, IL-36 binds to the IL-36 receptor, which then recruits an accessory protein, IL-1 receptor accessory protein (IL-1RAcP). This interaction forms a complex that initiates intracellular signaling pathways, including the NF-κB and MAPK pathways, leading to the production of inflammatory molecules.
How IL-36 Shapes the Immune Response
IL-36 activates various immune cells and amplifies inflammatory responses. It stimulates cells like keratinocytes, dendritic cells, and T cells, promoting immune cell activation and antigen presentation. For example, IL-36 can activate monocytes and upregulate the expression of other inflammatory cytokines such as IL-1α, IL-1β, and IL-6.
When IL-36 binds to its receptor on dendritic cells, it promotes their maturation and enhances antigen presentation, which is crucial for initiating adaptive immune responses. This activation leads to the production of cytokines like IL-12 and IL-23, which drive the differentiation of naive T cells into pro-inflammatory Th1 and Th17 cells. These Th1 and Th17 cells then produce inflammatory mediators like IFN-γ and IL-17A, further amplifying the immune response.
IL-36 signals the immune system to threats, contributing to host defense. In the skin, for instance, it aids first-line defense. This signaling leads to the recruitment of immune cells, particularly neutrophils, to the site of inflammation and the production of chemokines such as CXCL1, CXCL8, CXCL10, and CCL20. Sustained activation of this pathway, especially the IL-36-chemokine-neutrophil axis, is a feature in conditions of uncontrolled inflammation.
IL-36 and Conditions of Chronic Inflammation
Dysregulation of IL-36 signaling is linked to various chronic inflammatory conditions, particularly generalized pustular psoriasis (GPP). GPP is a rare, chronic inflammatory skin disorder characterized by widespread superficial sterile pustules and skin redness. In GPP, unopposed or dysregulated IL-36 signaling activates epidermal keratinocytes in an auto-amplification loop, leading to the release of inflammatory products.
Genetic mutations in the gene encoding IL-36Ra can lead to uncontrolled IL-36 activity, which is associated with GPP. This overactivity contributes to GPP symptoms by promoting the production of inflammatory cytokines like CXCL8, TNF-α, IL-1, and IL-23, and by stimulating the accumulation of neutrophils in the skin lesions. The pathogenic role of IL-17A, which is also elevated in pustular psoriasis, is further amplified by IL-36.
Beyond skin conditions, IL-36 is also implicated in other chronic inflammatory conditions. In inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, IL-36 cytokine expression is elevated in inflamed colonic tissues, particularly IL-36α and IL-36γ, and correlates with the degree of inflammation. While IL-36 can exacerbate chronic intestinal inflammation and contribute to fibrosis, it may also play a protective role in acute intestinal inflammation by promoting healing and epithelial cell proliferation after mucosal injury. In rheumatoid arthritis (RA), a chronic autoimmune disease affecting joints, IL-36α, IL-36β, IL-36γ, and IL-36Ra are upregulated in the synovium. IL-36 can stimulate synovial fibroblasts to produce IL-6 and IL-8, contributing to joint inflammation.
Developing Treatments That Target IL-36
Understanding IL-36’s role in inflammation has paved the way for new therapeutic approaches. Strategies involve blocking the IL-36 receptor or neutralizing IL-36 to reduce its pro-inflammatory effects. These treatments aim to interrupt the signaling cascade initiated by IL-36, reducing inflammation and alleviating disease symptoms.
Monoclonal antibodies are being developed to target IL-36. For instance, spesolimab is a humanized monoclonal antibody that specifically binds to the IL-36 receptor, preventing the binding of IL-36 agonists and antagonizing IL-36 signaling. This therapy has shown results in clinical trials for generalized pustular psoriasis, demonstrating improvements in skin lesions. Imsidolimab is another monoclonal antibody targeting IL-36R currently being evaluated in clinical studies. By blocking the IL-36 receptor, these treatments aim to reduce the production of downstream pro-inflammatory cytokines, suppress dendritic cell maturation, and decrease T cell activation, mitigating pathological inflammation.