Interleukin-33 (IL-33) is a powerful signaling molecule belonging to the Interleukin-1 family. Its primary function is to regulate the body’s immune response, orchestrating defenses against external threats and maintaining stability within tissues. As a cytokine, IL-33 influences both the innate and adaptive branches of immunity. This molecule possesses a striking dual nature: while its release is fundamental for initiating protective reactions and promoting tissue healing, chronic or excessive signaling can drive persistent inflammatory diseases.
IL-33: The Immune System’s Alarm Signal
IL-33 is primarily stored in the nucleus of cells that form the body’s protective barriers, such as epithelial cells lining the lungs and gut, and endothelial cells lining blood vessels. Unlike most other cytokines that are actively secreted, IL-33 remains sequestered within the cell nucleus under normal, healthy conditions. This nuclear storage prevents unnecessary immune activation when no threat is present.
The molecule is released passively into the extracellular space when the cell experiences mechanical stress, trauma, or necrosis (uncontrolled cell death). This damage-induced release mechanism defines IL-33 as an alarmin, a danger signal that immediately alerts the immune system to tissue injury. The full-length form of IL-33 is biologically active upon release, though it can be further processed by inflammatory proteases to generate highly potent forms.
Once released, IL-33 exerts its effect by binding to its specific receptor complex on the surface of target immune cells. This complex is composed of the primary receptor ST2 and the co-receptor, Interleukin-1 Receptor Accessory Protein (IL-1RAcP). The ST2 receptor is constitutively expressed on a variety of immune cells, including basophils, mast cells, and Group 2 Innate Lymphoid Cells (ILC2s).
The binding of IL-33 to the ST2/IL-1RAcP complex triggers a cascade of intracellular signals within the target cell. This binding event translates the physical signal of tissue damage into a targeted immune response. The process ensures that the immune reaction is localized and proportionate to the severity of the damage, setting the stage for either defense or repair depending on the context.
Essential Functions in Healthy Immunity
The immediate action of IL-33 upon release is to initiate a robust Type 2 immune response. This protective mechanism defends the host against large, extracellular parasites like helminth worms. By activating ILC2s and other cells, IL-33 helps expel these invaders by promoting processes like enhanced mucus production and increased gut motility.
Beyond pathogen defense, IL-33 helps maintain the physical integrity and stability of tissues (homeostasis). The molecule plays a significant role in promoting tissue repair and wound healing following injury to barrier surfaces like the skin, lungs, and intestines. This reparative function is mediated by its effect on specific immune cell populations.
IL-33 signaling activates regulatory T (Treg) cells, which temper excessive inflammation. These Treg cells, along with ILC2s, produce a growth factor called Amphiregulin (AREG). AREG directly stimulates the regeneration of damaged epithelial cells, facilitating the mending of the tissue barrier after a breach.
This protective function extends to metabolic health, where IL-33 helps preserve homeostasis within adipose (fat) tissue. It contributes to suppressing chronic inflammation that can arise in obesity, thereby preserving the body’s sensitivity to insulin. IL-33 functions as a restorative signal, ensuring that the immune response resolves effectively.
IL-33’s Contribution to Inflammatory Diseases
When the mechanism regulating IL-33 release or signaling becomes dysfunctional, its protective response can transform into a chronic pathological state. The continuous presence of extracellular IL-33 leads to persistent activation of the Type 2 immune pathway, driving various chronic inflammatory and allergic diseases. This misdirected signaling underlies conditions where the immune system overreacts to harmless environmental triggers.
A primary example is allergic asthma, where elevated levels of IL-33 are found in the airways. Epithelial cells in the bronchial lining release IL-33 in response to allergens or irritants, which potently activates ILC2s. The activated ILC2s rapidly produce large quantities of Type 2 inflammatory cytokines, specifically Interleukin-5 (IL-5) and Interleukin-13 (IL-13).
IL-5 is a major driver of eosinophil accumulation in the lungs, while IL-13 promotes mucus overproduction and contributes to the airway hyper-responsiveness characteristic of asthma attacks. This IL-33-driven cascade perpetuates chronic inflammation, structural changes, and narrowing of the airways.
Similarly, in atopic dermatitis (eczema), IL-33 is significantly upregulated in the epidermis of lesional skin. The skin’s barrier function is often compromised, which triggers the release of IL-33 from damaged keratinocytes. This localized release promotes the accumulation of ST2-expressing ILC2s in the skin.
These ILC2s subsequently secrete IL-5 and IL-13, which drives the infiltration of eosinophils and the persistent skin inflammation seen in eczema. The continuous cycle of barrier damage and IL-33 release sustains the chronic itching and dermatitis. Genetic variations in the ST2 receptor have also been linked to a higher susceptibility for developing atopic diseases.
The pathological role of IL-33 extends beyond allergic disorders, with emerging evidence linking it to other chronic inflammatory conditions. For instance, elevated IL-33 signaling has been implicated in certain forms of inflammatory bowel diseases, where it contributes to chronic inflammation in the intestinal lining. This wide range of involvement highlights the dysregulated IL-33 pathway as a common factor in various persistent inflammatory states.