The central role of IL-33/IL-1RL1 pathway in asthma: From pathogenesis to intervention

A K Saikumar Jayalatha; L Hesse; M E Ketelaar; G H Koppelman; M C Nawijn

doi:10.1016/j.pharmthera.2021.107847

The central role of IL-33/IL-1RL1 pathway in asthma: From pathogenesis to intervention

Pharmacol Ther. 2021 Sep:225:107847. doi: 10.1016/j.pharmthera.2021.107847. Epub 2021 Apr 2.

Authors

A K Saikumar Jayalatha¹, L Hesse¹, M E Ketelaar², G H Koppelman³, M C Nawijn⁴

Affiliations

¹ University of Groningen, University Medical Centre Groningen, Department of Pathology and Medical Biology, Laboratory of Experimental Pulmonology and Inflammation Research (EXPIRE), Groningen, the Netherlands; University of Groningen University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands.
² University of Groningen, University Medical Centre Groningen, Department of Pathology and Medical Biology, Laboratory of Experimental Pulmonology and Inflammation Research (EXPIRE), Groningen, the Netherlands; University of Groningen University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands; University of Groningen University Medical Centre Groningen, Beatrix Children's Hospital, Department of Paediatric Pulmonology and Paediatric Allergology, Groningen, the Netherlands.
³ University of Groningen University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands; University of Groningen University Medical Centre Groningen, Beatrix Children's Hospital, Department of Paediatric Pulmonology and Paediatric Allergology, Groningen, the Netherlands.
⁴ University of Groningen, University Medical Centre Groningen, Department of Pathology and Medical Biology, Laboratory of Experimental Pulmonology and Inflammation Research (EXPIRE), Groningen, the Netherlands; University of Groningen University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands. Electronic address: m.c.nawijn@umcg.nl.

PMID: 33819560
DOI: 10.1016/j.pharmthera.2021.107847

Abstract

Interleukin-33 (IL-33), a member of the IL-1 family, and its cognate receptor, Interleukin-1 receptor like-1 (IL-1RL1 or ST2), are susceptibility genes for childhood asthma. In response to cellular damage, IL-33 is released from barrier tissues as an 'alarmin' to activate the innate immune response. IL-33 drives type 2 responses by inducing signalling through its receptor IL-1RL1 in several immune and structural cells, thereby leading to type 2 cytokine and chemokine production. IL-1RL1 gene transcript encodes different isoforms generated through alternative splicing. Its soluble isoform, IL-1RL1-a or sST2, acts as a decoy receptor by sequestering IL-33, thereby inhibiting IL1RL1-b/IL-33 signalling. IL-33 and its receptor IL-1RL1 are therefore considered as putative biomarkers or targets for pharmacological intervention in asthma. This review will provide an overview of the genetics and biology of the IL-33/IL-1RL1 pathway in the context of asthma pathogenesis. It will discuss the potential and complexities of targeting the cytokine or its receptor, how genetics or biomarkers may inform precision medicine for asthma targeting this pathway, and the possible positioning of therapeutics targeting IL-33 or its receptor in the expanding landscape of novel biologicals applied in asthma management.

Keywords: Asthma; Epithelial cells; Genetics; IL-1RL1; IL-33; Immune cells; Pharmacotherapy.

Publication types

Review

MeSH terms

Asthma* / drug therapy
Asthma* / genetics
Asthma* / pathology
Child
Humans
Interleukin-1 Receptor-Like 1 Protein* / genetics
Interleukin-1 Receptor-Like 1 Protein* / metabolism
Interleukin-33* / genetics
Interleukin-33* / metabolism
Signal Transduction*

Substances

Interleukin-1 Receptor-Like 1 Protein
Interleukin-33