An innate sensing and signaling mechanism triggered in people by a broad array of environmental allergens including fungi, insects, and mites, has been discovered in new research led by scientists at Cincinnati Children’s Hospital Medical Center. The built-in rapid reaction system may hold the key to understanding and treating human allergies.

Studies in immunology over the past two decades have discovered how the innate immune system senses bacteria and viruses, but how allergens are sensed has remained enigmatic.

Featured in the journal Nature Immunology on September 16, 2021, the article titled “Environmental allergens trigger type 2 inflammation through ripoptosome activation” details how the body’s type 2 innate immune response system works when exposed to allergens. The results suggest the common biological response platform if controlled pharmacologically could help treat a wide range of allergies.

“Disrupting this allergen sensing pathway could provide a unique opportunity to counteract type 2 immunity and alleviate allergic inflammation,” says Marc Rothenberg, MD, PhD, Director of the Division of Allergy and Immunology at Cincinnati Children’s Hospital Medical Center and senior author of the paper.

“The discovery of this surprising mechanism is the most important breakthrough in understanding how the innate immune system senses allergens to initiate a type 2 response and subsequent allergic inflammation,” says Chandrashekhar Pasare, DVM, PhD, a senior author of the paper.

Earlier studies have shown several allergens upon breaking through the first line of defense—the epithelial barrier of mucosal membranes—induces interleukin-33 (IL-33), a DNA-binding nuclear factor, and a cytokine. The current study pins down the mechanisms at work in the process.

IL-33, generally released following cell damage or death and processed in the extracellular matrix, plays a central role in type-2 immunity.

“This breakthrough was made possible by new insights into the role of ripoptosome signaling and caspases in allergic inflammation,” says Michael Brusilovsky, MMedSc, PhD, first author of the paper.

RIPIL33 is an epithelial allergen sensing pathway, triggered in people by a broad array of environmental allergens [Cincinnati Children’s Hospital Medical Center]
In diverse epithelial cells, environmental allergens trigger the activity of an interlocked set of cell death-inducing signals called the ripoptosome. This signaling hub includes numerous components. Key among these for allergic inflammatory reactions is an enzyme called caspase 8. Since IL-33 is processed or ripped by the ripoptosome-led mechanism, the investigators call the pathway RipIL-33.

The novel RIPIL-33 pathway assembles following exposure to various unrelated environmental allergens and processes IL-33 into an active form within the cell to facilitate cellular recognition of the allergen.

The authors conduct studies in mice where they inhibit the activity of the caspase 8 enzyme or remove the IL-33 gene and demonstrate reduced response to allergen exposure and limited bronchial inflammation in the lungs.

Clinical data corroborated that human allergic inflammation also involves ripoptosome activation and IL-33 maturation. “In the human allergic disease eosinophilic esophagitis we found that ripoptosome activation markers and mature IL-33 levels dynamically correlated with the degree of esophageal eosinophilia and disease activity,” the authors note.

In future studies, the team will further confirm the role of the RipIL-33 pathway in human allergic inflammation and identify existing or new drugs that can target this novel pathway to relieve uncontrolled inflammation in response to a variety of environmental allergens.

“We propose that disrupting caspase 8–ripoptosome activation provides a unique potential entry point to counteract type 2 immunity and alleviate allergic inflammation,” the authors conclude.

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