Role of Interleukin-1 Receptor-Like 1 (ST2) in Cerebrovascular Disease

Abstract

Following both ischemic and hemorrhagic stroke, innate immune cells initiate a proinflammatory response that further exacerbate tissue injury in the acute phase, but these cells also play an important reparative role thereafter. Numerous cytokines and signaling pathways have been implicated in driving the deleterious proinflammatory response, but less is known about the mediators that connect the initial vascular injury to the systemic immune response and the relationship between proinflammatory and reparative immune responses. The Interleukin-33 (IL-33) and serum stimulation-2 (ST2) axis is an interleukin signaling pathway that is a prime candidate to fulfill this role. In this review, we describe the biology of the IL-33/ST2 system, present evidence that its soluble decoy receptor, soluble ST2 (sST2), plays a key role in secondary neurologic injury after stroke, and discuss this in the context of the known role of IL-33/ST2 in other disease.

Keywords: Brain edema; Inflammation; Soluble ST2; Stroke.

Figure 1.. The IL-33/ST2 pathway and its conceptual role following ischemic stroke.

A) The main components of the IL-33/ST2 axis are shown. Once released, IL-33 binds the ST2L receptor and the IL-1RAP co-receptor. ST2L and IL-1RAP then recruit intracellular MyD88, which prevents is activity in TLR4-mediated, pro-inflammatory signaling. In this model, IL-33 is anti-inflammatory and when sST2 level is high, this prevents IL-33 signaling. The decoy receptor sST2 is therefore pro-inflammatory. B) A conceptual depiction of the phases of the inflammatory response after acute CNS injury. Immune cells are activated during the initiation phase, when DAMPs are released and bind to TLR4 receptors. In the first few days after CNS injury, the pro-inflammatory immune response is further amplified, which is characterized by systemic release of cytokines and recruitment of peripheral innate immune cells, including neutrophils and macrophages. The activity of these cells leads to blood-brain barrier disruption and brain edema. Subsequently, this is followed by a resolution phase where an anti-inflammatory immune response promotes the clearance of debris and establishes a substrate for subsequent neural repair. Existing data suggests that sST2 can amplify the pro-inflammatory phase and potential forestall the transition to reparative immune responses, making this pathway of interest from a therapeutic standpoint. Images created with BioRender.com.