The discovery of a new signaling pathway raises hope for finding new ways of controlling allergic inflammation

October 15, 2021

Summary: Type 2 immunity plays a vital role in sensing allergens and parasites and initiating an immune response against them. It causes an influx of eosinophil, and early release of IL-33 is characteristic of such a response. However, its dysregulation is associated with allergic conditions like asthma, eczema, rhinitis, and even anaphylactic shock. To date, researchers know little about how type 2 immunity senses allergens and initiates an immune response. However, now researchers have found activation ripoptosome pathway plays a critical role in these allergic reactions, causing a cascade of actions leading to increased IL-33 release, eosinophilia, and other changes. Researchers have named this pathway as RipIL-33 pathway, and blocking the pathway may be one of the strategies to managing these allergic reactions.

Keywords:type 2 immunity, allergy, asthma, eczema, atopic dermatitis, IL-33 ripoptosome, RipIL-33

It is known that two distinct types of immune responses exist that help fight infections, parasites, and other invaders. Type 1 T helper lymphocytes initiate a type 1 immune response that helps initiate phagocytic activity and thus neutralize infections like those caused by bacteria1.

Whereas type 2 helper lymphocytes sense foreign bodies, parasites, initiate antibody response, and greater influx of eosinophils, thus helping get rid of foreign antigens. Such a response is highly helpful in overcoming parasitic infections. However, the dysregulation of this immune reply to large foreign materials or parasites also causes allergic conditions like eczema, rhinitis, asthma, and even anaphylactic shock2.

Early studies also helped understand that cytokine Interleukin 33 (IL-33) release occurs relatively early in the immune response to allergens. These high levels of IL-33 cause inflammation. However, to date, researchers did not fully understand how this IL-33 release is initiated in type 2 immune response or the mechanism behind allergen sensing by immune cells like type 2 helper cells3.

The discovery of a new signaling pathway may help prevent allergic inflammation

Researchers already knew a lot about type 2 immune response and the role of its dysregulation in various allergic conditions. They also know that IL-33 plays a vital role in this immune response and in inflammation that occurs in different allergic conditions.

However, few researchers still did not know few things. For example, they knew how immunity senses the pathogens and the resulting immune response. But they did not know how the body senses allergens leading to allergic reactions. This discovery may help explain what triggers the allergic reaction in response to insects, fungi, mites, and other allergens.

The new study discovered the new allergen sensing pathway in the body called the ripoptosome pathway. In the study, researchers found that allergens activated molecular switch present on cell membranes called caspase 8, which in turn activates the ripoptosome pathway leading to increased production of IL-33. Thus, researchers have named this pathway “RipIL-33.” Once the IL-33 is released through this pathway, it causes increased activity of mast cells, lymphocytes, eosinophils, and consequently causing allergic inflammation.

Thus, researchers think that since they have found the switch that initiates this cascade of reactions, it means that blocking this switch may help prevent inflammation caused by allergens.

In the experimental study,the researcher blocked the activity of caspase 8 in mice. In addition, they found that it could considerably help reduce the inflammatory response to allergens, reducing the inflammation of bronchi and lungs in the mice model.

Researchers have further found that in allergic conditions like eosinophilic esophagitis (EoE), there is a marked activation of ripoptosome and mature IL-33. Further, they found that a higher level of activity of these pathways was directly related to the disease severity.

These findings may be instrumental in finding treatment for conditions like asthma and atopic dermatitis, as science has struggled to control these conditions adequately.


1. Spellberg B, Edwards JE Jr. Type 1/Type 2 Immunity in Infectious Diseases. Clinical Infectious Diseases. 2001;32(1):76-102. doi:10.1086/317537

2. Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019;16(3):225-235. doi:10.1038/s41423-019-0210-8

3. Nechama M, Kwon J, Wei S, et al. The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation. Nat Commun. 2018;9(1):1603. doi:10.1038/s41467-018-03886-6

4. Brusilovsky M, Rochman M, Rochman Y, et al. Environmental allergens trigger type 2 inflammation through ripoptosome activation. Nat Immunol. 2021;22(10):1316-1326. doi:10.1038/s41590-021-01011-2

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