Role of the soluble IL-33 receptor in osteoarthritis and type-1 versus type-2 T-cell responses

Principle Investigator

Scientific interest within the context of the graduate college:

Alarmins can be used as markers for pathologies even prior to obvious onset of disease. Moreover, interference with alarmins and their signaling pathways provides a powerful tool for the manipulation of several types of diseases (Liew et al., Nat Rev Immunol. 2016; Peine et al., Trends Immunol. 2016).

Project description:

Introduction: Recently we reported on the discovery of a type-1 immunity-restricted promoter of the IL-33 receptor gene ST2. Transcription of ST2 starting from this promoter is essential for CD8+ cytotoxic and CD4+ T-helper-1 cell responses to virus infection (Brunner et al., Nat. Immunol. 2024). During transcription of ST2 also a short isoform lacking the transmembrane domain is generated by alternative polyadenylation. This soluble IL-33 receptor sST2 is assumed to act as a decoy receptor for IL-33. However, its roles in osteoarthritis and type-1 versus type-2 T-cell responses remain enigmatic.

Aim 1: In this project we plan to use our newly generated mouse strains lacking the soluble IL-33 receptor to investigate the relevance of soluble ST2 for the generation and progression of osteoarthritis. Osteoarthritis will be induced in the relevant mouse strains either by surgery (destabilization of the medial meniscus (DMM) model) or spontaneously by aging of the mice (Shen et al., Proc Natl Acad Sci USA. 2023).

Aim 2: In another line of experiments we want to study the role of soluble ST2 in type-1 versus type-2 T-cell responses. Here the relevant mouse strains will either be infected with viruses to generate type-1 T-cell responses or they will be challenged by an airway inflammation model that triggers type-2 immunity. We will assess the effects on T-cell differentiation and expansion, viral clearance, and immunopathology.

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