Relationships between schizophrenia and the alarmins interleukin-33 (IL-33), soluble receptor of interleukin-33 (sST2) and the ratio IL-33/sST2. A systematic review

Schizophrenia is a multi-aetiologic disease. Inflammation have recently been involved in its pathophysiology. Recent research suggests that inflammation may be a key factor in its pathophysiology. Alarmins, interleukin-33 (IL-33), its soluble receptor sST2 and the ratio IL-33/sST2, have been investigated as neuroinflammation biomarkers. However, data on alarmins in schizophrenia remain scarce and conflicting, with findings varying across studies. The aim of this systematic review consists of analysing the relationships between IL-33, its sST2 and the ratio IL-33/sST2 in schizophrenia. The authors follow the PRISMA recommendations. The keywords IL-33 OR interleukin-33 OR sST2 OR soluble ST2 OR IL-33/sST2 were intersected with the Boolean operator AND with the key words schizophrenia OR psychosis OR psychotic disorder. The search was carried out in PubMed/MEDLINE, EMBASE, PsycInfo, Scopus and Web of Science. Despite the initial search yielding 115 publications, only five studies met inclusion criteria, comprising 107 healthy controls (HC) and 267 patients, highlighting the limited data available. IL-33 and its sST2 were significantly increased in patients with an acute relapse compared to HC, while patients in clinical remission had levels comparable to those of HC. No consistent relationship was found between antipsychotic treatment and IL-33 or sST2 levels, raising questions about the influence of medication on these markers. The quality of evidence was low to moderate (10 ± 1, with an evidence level of 3 ± 0, according to the Oxford Centre for Evidence-Based Medicine criteria). This systematic review highlights the possibility that IL-33 and sST2 play a role in the pathophysiology of schizophrenia, particularly in relation to neuroinflammation and neuronal dysfunction. However, the controversial and inconsistent findings suggest the need for larger, well-controlled studies. Additionally, the lack of mechanistic insight into how these alarmins contribute to schizophrenia pathophysiology remains a critical gap. Understanding the impact of IL-33 and sST2 on neuroinflammatory pathways could provide new therapeutic targets. Future research should also explore whether these markers can aid in early diagnosis or monitoring treatment response.