Fig. 3

IL-33-ST2 pathway in sepsis. a Mechanism of recognizing LPS. LPS, a component of the outer membrane of Gram-negative bacteria, is recognized by the MD-2/TLR4 complex and forms a TLR4 homodimer after interaction. Next it can activate two different pathways. The activation of TRIF-dependent signaling pathway produces type I IFN, and Myd88-dependent signaling pathway can produce pro-inflammatory cytokines by mediating the activation of NF-kB. Additionally, the NLR family includes a central nucleotide-binding domain and C-terminal leucine-rich repeats. NOD-1 and NOD-2 whose N-terminal contain protein-binding motifs CARDs also active NF-κB inducing pro-inflammatory cytokines. b IL-33-ST2 pathway in lungs with sepsis acts on neutrophils. In sepsis, the production of pro-inflammatory factors leads to increased expression of E selectin, which results in neutrophil infiltration in the lungs. At the same time, there is a decrease in neutrophil margination, rolling and transmigration, but an increase in adhesion. This leads to vascular obstruction and tissue ischemia. Bacteria can upregulate iNOS expression via TLR on neutrophils. And phosphoinositide 3-kinase (PI3K) can activate iNOS to increase GRK2 expression, which leads to CXCR2 internalization. However, IL-33 can block GRK2 expression through ST2 and maintain expression of CXCR2, thereby promoting the migration of neutrophils for bacterial clearance. c IL-33-ST2 pathway in lungs with sepsis acts on ILC2s. IL-33 acts on BM-derived ILC2p via ST2 to induce GRK2 expression and subsequently downregulate cell surface expression of CXCR4, thereby reducing ILC2p retention in the BM and promoting ILC2 expansion in the lung. While LPS can have the opposite effect by blocking GRK2 expression through TLR. The increased ILC2s in the lungs secrete IL-9, which attenuates caspase-1 activation to prevent pyroptosis in the lung endothelium, thus protecting from ALI or sepsis. In addition, ILC2 secretes IL-5 and IL-13 to promote the polarization of M2 macrophages, and IL-10 to promote the expansion of Treg, thus causing immunosuppression. PD-L1 expression levels are enhanced by pro-inflammatory cytokines, while the PD-1/PD-L1 pathway negatively regulates ILC2. The balance between PD-1/PD-L1 signaling and the IL-33/ST2 signaling influences the level of IL-13 production, which was proved to play a protective role in sepsis