Mediators of Inflammation

Review Article

Critical Roles of IL-33/ST2 Pathway in Neurological Disorders

Table 1

Involvement of IL-33/ST2 pathways in variants of CNS diseases.


Disorder	Findings	References

Alzheimer’s disease	(i) IL-33 mRNA and protein expression was increased by PAMPs in CNS glia.	[19]
	(ii) IL-33-stimulated and IL-33-amplified mast cells directly induce arginase I, CCL17, CCL11, & TNF-α in CNS glia.	[73]
	(iii) IL-33 expression is reduced in the brains.
	(iv) IL-33 decreases the secretion of Aβ₄₀ peptides when overexpressed.
	(v) Dose-dependent IL-33 induces proliferation of microglia and stimulates the production of IL-1β, TNF-α, & IL-10.
	(vi) IL-33 enhanced the production of CCL2, CCL3, CCL5, CXCL10, nitric oxide, and phagocytic activity of microglia.	[67]
	(vii) IL-33 and ST2 expression was highly expressed in βA plaque, NFTs, and glial cells in the AD brains.	[72]
	(viii) IL-33 and ST2⁺ cells increased in the brain.
	(ix) IL-33 reduced soluble βA levels and plaque accumulation via βA phagocytic activity.	[16]
	(x) IL-33 modulation polarised microglia/macrophages and reduced IL-1β, IL-6, & NLRP3 in the brain.

Multiple sclerosis	(i) IL-33 was highly expressed in peripheral blood and CNS and plague areas in MS brains.	[80, 81]
	(ii) IL-33 plasma level was elevated compared with controls.	[81]
	(iii) IL-33 plasma level was reduced in MS patients treated with IFN-β-1a.
	(iv) Intracellular IL-33 and OAS1, GATA3, & PMAIP1 were highly expressed.	[79]
	(v) IL-33 and HDAC were highly induced in RRMS patients.
	(vi) IL-33 might be regulating gene expression in RRMS.
	(vii) IL-33 and ST2 expressions were enhanced in the lesions of acute and chronic MS patients compared to healthy controls.	[17]
	(viii) IL-33 might inhibit CNS myelination.

Experimental cerebral malaria	(i) IL-33 induces ILC2 expansion via IL-4, IL-5, & IL-13 and polarises M2 macrophages and Tregs.	[24]
	(ii) IL-33-treated Treg^−/− mice were unable to resist ECM; IL-33-treated mice reduced parasitaemia at the early phase of infection.
	(iii) ST2^−/− mice and WT mice exhibited no changes in parasitaemia and brain parasite load.	[15]
	(iv) ST2^−/− mice survived >20 days compared with WT mice with features of ECM.
	(v) ICAM-1, CXCR3, and LT-α expression reduced and diminished both CD4⁺ and CD8⁺ T-cell recruitment and sequestration.
	(vi) IL-33^−/− and WT mice exhibited no prominent changes in parasitaemia and survival rate.	[89]
	(vii) TSLP mRNA expression was significantly decreased as compared to IL-33 and IL-25 at the late stage of infection.