The Functional Roles of IL-33/ST2 Axis in Ocular Diseases

Table 1

Involvement of Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis in ocular diseases.

Disease	Findings	Refs
Allergic eye disease	IL-33 induced recruitment and ST2 expression of eosinophils and promoted T helper 2 (Th2) cytokines expression in allergic conjunctivitis (AC) mice model.	[73, 81]
	IL-33 was upregulated in the conjunctival giant papillae of atopic keratoconjunctivitis (AKC).; IL-33/ST2 axis induced the phosphorylation of p38 mitogen-activated protein kinases (MAPK) and IL-13 mRNA induction in mast cells.	[74]
	The induction of proallergic IL-33 was triggered by specific Toll-like receptors (TLR) ligands through innate immunity signaling pathways in corneal epithelium.	[75]
	IL-33/ST2 mediated proallergic responses via nuclear factor kappa B (NF-κB) signaling pathway and induced the production of proallergic cytokines and chemokines in human corneal epithelial cells (HCECs).	[76]
	Overexpression of IL-33 in keratinocytes induced the onset of AKC, accompanying the activation of corneal group 2 innate lymphoid cells (ILC2) and the release of Th2 cytokines.	[77]
	IL-33 mRNA and protein increased in conjunctival epithelial tissue in AC mice.; Eosinophil and basophil infiltration and Th2 cytokines expression decreased in the IL-33 knockout mice.	[78, 79]
	IL-33 augmented CD4+, ST2+, or IL1RAP+ cells infiltration and Th2 cytokines expression in AC mice model.; Clinical and molecular changes decreased in TLR4 deficient or MyD88 knockout mice.	[80]
	Total IgE concentration in serum and mast cells infiltration in conjunctiva increased in AC mice model.	[81]
Keratitis and corneal regeneration	ST2 mRNA and protein levels elevated in the Pseudomonas aeruginosa- (P. aeruginosa-) infected cornea in Th-2 responsive mice.; Blocking ST2 signaling led to susceptible to P. aeruginosa-induced keratitis.	[83]
	IL-33 mRNA and protein levels elevated in the P. aeruginosa-infected cornea in Th-2 responsive mice.; Stimulating IL-33 signaling led to resistance to P. aeruginosa-induced keratitis.	[84]
	IL-33 mRNA and protein levels elevated in the Aspergillus fumigatus-infected cornea in human, mice, and HCECs.; IL-33/ST2/p38 MAPK axis amplified the proinflammatory responses induced by Aspergillus fumigatus in HCECs.	[85]
	IL-33/ST2 induced the production of inflammatory mediators (tumor necrosis factor-α, IL-1β, IL-6, and IL-8), while ST2 antibody, soluble ST2, NF-𝜅B activation inhibitor and inhibitor of NF-κB inhibitor suppressed the signaling.	[86]
	IL-33 increased in cornea tissue after corneal epithelial wounding, promoting the number and function of corneal ILC2s in the healing process.	[87]
Dry eye disease (DED)	IL-33 and ST2 protein increased in the conjunctival impression cytology of DED patients.; IL-33 mRNA and protein elevated in DED cell model.	[89]
	IL-33 concentration elevated in tears of DED patients.	[90]
	Elevated IL-33 level in tears of DED patients was positively related to increased Th2 cytokines (L-4, IL-5, and IL-13) and clinical severity.	[89, 91]
Uveitis	Upregulated IL-33/ST2 axis promoted macrophages polarization, altered the cytokines production profile, and reduced the disease severity in autoimmune uveitis mice.	[93]
	Serum IL-33 level increased in Behçet uveitis patients compared to Behçet patients without uveitis.	[94]
	A single nucleotide polymorphism-rs3773978 in gene interleukin 1 receptor like 1 significantly was associated with acute anterior uveitis (AAU) in Chinese population.	[95]
	No differences of IL-33 level in aqueous humor and serum were found among HLA-B27 associated AAU patients, idiopathic AAU patients, and control group.	[96]
Vitreoretinal diseases	Increased IL-33/ST2 signaling was closely correlated with the enhanced expression levels of IL-1β, Th1, and Th2 cytokines in eyes of Toxoplasma gondii-infected mice.	[97]
	Upregulated mRNA levels of triggering receptor expressed on myeloid cells-1 and TLRs were correlated with increased IL-33/ST2 signaling in damaged retina and choroid of Toxoplasma gondii-infected mice.	[98]
	IL-33 was highly released by Müller cells in the lesion area in age-related macular degeneration patients.; Upregulated IL-33/ST2 signaling in Müller cells resulted in downstream cytokines and chemokines release, photoreceptor cell loss, and mononuclear phagocytes recruitment after light exposure.	[101]
	IL-33 and ST2 expression elevated in retinal pigment epithelium cells of age-related macular degeneration cell model.; IL-33/ST2 signaling induced inflammatory cytokines secretion via MAPK, c-Jun N-terminal kinase, extracellular regulated protein kinases, NF-κB pathways.	[102]
	IL-33 production, retinal vascular progression, and subretinal fibrosis formation decreased after antiendoglin and/or antivascular endothelial growth factor-A antibody therapy.	[103]
	IL-33/ST2 was upregulated by Toll-like receptor activation or hypoxic condition and can subsequently protect retina degeneration and choroidal neovascularization development.	[105]
	Plasma IL-33 increased in patients with polypoidal choroidal vasculopathy, together with diminished Tregs and enhanced Th2-like Tregs.; The level of IL-33 was positively correlated with the percentage of Th2-like Tregs.	[106]
	IL-33 increased in the detached retina in mice. IL-33 deficiency resulted in exacerbated and sustained retinal inflammation, together with enhanced retinal degeneration and gliosis.	[107]
	Serum IL-33 increased in infants with retinopathy of prematurity, and greatly reduced after laser treatment.	[108]
	No significant changes were observed in both percent detectable and level of IL-33 in the serum, vitreous, and aqueous humor of proliferative diabetic retinopathy patients.	[109, 110]
Neuromyelitis optica spectrum disorder	Upregulated level of serum IL-33 was associated with disease status and relapse rate in neuromyelitis optica spectrum disorder.	[111]