Interleukin-33/suppression of tumorigenicity 2 signaling in gastric injury: From mechanistic validation to spatiotemporal precision

Table 1 Function of the interleukin-33/suppression of tumorigenicity 2 signaling pathway in different cell types

Cell type	Key molecules	Function
Mast cell	TNF-α, IL-1β, IL-6, IL-13, VEGF	Amplification of inflammation, vascular responses, and tissue remodeling; increased cell adhesion and immune cell crosstalk
Th2 cell	IL-4, IL-5, IL-10, IL-13	IL-33 exerts a chemotactic effect on Th2 cells; it promotes the polarization of naive T cells toward the Th2 pathway
Treg cell	FoxP3, ST2	IL-33/ST2 axis promotes Treg expansion; suppresses IL-17 and IFN-γ production
Eosinophil	IL-4, IL-5, IL-9, IL-13, GM-CSF	Dual involvement in pro-inflammatory and immunomodulatory functions
ILC2	IL-6, IL-4, IL-5, IL-9, IL-13	Central amplifier of Type 2 immune responses
Dendritic cell	IL-1β, IL-6, TNF-α, CD80, CD86	IL-33 promotes the polarization of naïve T cells toward Th2 cells by activating dendritic cells
Fibroblast	ERK, p38 MAPK	IL-33 activates fibroblasts (ERK/p38 MAPK–dependent) to produce chemokines and promote eosinophil infiltration
B cell	IL-4R	IL-33 activates B cells during delayed-type hypersensitivity and increases IL-4R+ B cells, facilitating IgE production
Macrophage	IL-1β, IL-6, IL-10, VEGF, MMP9	IL-33-induced STAT1 signaling correlates with IFN-γ output

TNF-α: Tumor necrosis factor alpha; IL: Interleukin; VEGF: Vascular endothelial growth factor; FoxP3: Forkhead box P3; ST2: Suppression of tumorigenicity 2; IFN-γ: Interferon gamma; GM-CSF: Granulocyte-macrophage colony-stimulating factor; CD80: Cluster of differentiation 80; CD86: Cluster of differentiation 86; ERK: Extracellular signal-regulated kinase; p38 MAPK: P38 mitogen-activated protein kinase; IL-4R: Interleukin-4 receptor; MMP-9: Matrix metalloproteinase-9; STAT1: Signal transducer and activator of transcription 1.

Table 2 Current advances in molecular imaging of the interleukin-33/suppression of tumorigenicity 2 signaling pathway

Target	Imaging	Label	Research	Disease	Year	Notes	Ref.
IL-33	NA	NA	Preclinical	Acute and chronic viral infection	2021	Although the GFP reporter gene was employed, no in vivo imaging was performed; only traditional fluorescence microscopy was utilized	Aparicio-Domingo et al[55]
ST2	NA	BODIPY	Preclinical	NA	2024	An IL-33 analog was conjugated to a fluorescent dye to bind to ST2. This was only performed at the cellular level without in vivo imaging; attempts at in vivo fluorescence imaging could be pursued	Reese et al[56]
ST2 L	NA	Luciferase reporter gene	Preclinical	Th2-mediated diseases	2001	Autofluorescence imaging is feasible, but the study did not perform in vivo imaging and only conducted ex vivo validation	Carter et al[57]
mTNF	Fluorescence imaging	FITC	Clinical	Crohn’s disease	2014	Detecting TNF to Predict Treatment Response in Crohn’s disease	Atreya et al[58]
CD11b	PET	NA	Preclinical	Gastric cancer	2022	In vivo real-time PET imaging of CD11b	Zhang et al[59]
VEGFR3	Fluorescence imaging	Cy5.5; IRdye800	Preclinical	Cancer lymphatic metastasis	2024	In vivo fluorescence imaging of VEGFR3	Shen et al[60]
caspase-3	MRI	NA	Preclinical	apoptosis-related diseases	2023	Lack of in vivo imaging in animal disease models	Xu et al[61]
MyD88	NA	eGFP, DsRed2	Preclinical	Bacterial Infection	2009	Achieved only at the cellular/lineage level	Hall et al[62]
AP-1	Fluorescence imaging	Luciferase reporter gene	Preclinical	Solar UV-induced inflammatory skin damage	2023	AP-1 is fused to the luciferase gene. The intensity of the fluorescence signal reflects AP-1 transcriptional activity	Snell et al[63]
Neutrophil elastase	Fluorescence imaging, photoacoustic imaging	Hemi-cyanine	Preclinical	Lung cancer	2022	Excitation fluorescence and photoacoustic imaging of human neutrophil elastase	Zhang et al[64]
STAT1	NA	GFP, RFP, luciferase reporter gene	Preclinical	Not a specific disease	2013	Achieved only at the cellular level, with potential for in vivo imaging	Samsonov et al[65]
Caspase-1	NA	TPETH	Preclinical	Inflammation-related diseases	2018	Failure to perform in vivo fluorescence imaging on animals	Lin et al[66]
Caspase-1	NA	Luciferase reporter gene	Preclinical	DSS-induced colitis and secondary neuroinflammation	2021	Fluorescence imaging was performed on excised tissue; no in vivo imaging was conducted	Talley et al[67]
IL-13	NA	eGFP	Preclinical	Allergic airwayinflammation	2016	It is believed that IL-33 regulates IL-13 production via ST2. The study primarily performed fluorescent detection of IL-13 in tissue sections, without conducting in vivo dynamic imaging	Piehler et al[68]
Caspase-3/7	NA	Luciferase reporter gene	Preclinical	Cancer	2018	Data from live imaging not displayed	Pal et al[69]

IL: Interleukin; ST2: Suppression of tumorigenicity 2; ST2 L: Suppression of tumorigenicity 2 ligand; CD11b: Cluster of differentiation 11b; VEGFR3: Vascular endothelial growth factor receptor 3; caspase-3: Cysteine-aspartic protease-3; MyD88: Myeloid differentiation primary response 88; AP-1: Activator protein 1; STAT1: Signal transducer and activator of transcription 1; caspase-1: Cysteine-aspartic protease-1; caspase-7: Cysteine-asparticprotease-7; PET: Positron emission tomography; MRI: Magnetic resonance imaging; NA: Not available; GFP: Green fluorescent protein; RFP: Red fluorescent protein.