Interleukin (IL)‐33, a member of the IL‐1 cytokine family, is an important modulator of the immune system associated with several immune‐mediated disorders. High levels of IL‐33 are expressed by the central nervous system (CNS) suggesting a potential role of IL‐33 in autoimmune CNS diseases. We have investigated the expression and function of IL‐33 in the development of experimental autoimmune encephalomyelitis (EAE) in mice. We report here that IL‐33 and its receptor ST2 (IL‐33Rα) are highly expressed in spinal cord tissue, and ST2 expression is markedly increased in the spinal cords of mice with EAE. Furthermore, ST2‐deficient (ST2^−/−) mice developed exacerbated EAE compared with wild‐type (WT) mice while WT, but not ST2^−/− EAE mice treated with IL‐33 developed significantly attenuated disease. IL‐33‐treated mice had reduced levels of IL‐17 and IFN‐γ but produced increased amounts of IL‐5 and IL‐13. Lymph node and splenic macrophages of IL‐33‐treated mice showed polarization toward an alternatively activated macrophage (M2) phenotype with significantly increased frequency of MR⁺PD‐L2⁺ cells. Importantly, adoptive transfer of these IL‐33‐treated macrophages attenuated EAE development. Our data therefore demonstrate that IL‐33 plays a therapeutic role in autoimmune CNS disease by switching a predominantly pathogenic Th17/Th1 response to Th2 activity, and by polarization of anti‐inflammatory M2 macrophages.

The role of IL‐33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate time‐dependent increase of endogenous IL‐33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL‐33 accelerated tumor growth and development of lung and liver metastases, which was associated with increased intratumoral accumulation of CD11b⁺Gr‐1⁺ TGF‐β1⁺ myeloid‐derived suppressor cells (MDSCs) that expressed IL‐13α1R, IL‐13‐producing Lin⁻Sca‐1⁺ST2⁺ innate lymphoid cells (ILCs) and CD4⁺Foxp3⁺ST2⁺IL‐10⁺ Tregs compared to untreated mice. Higher incidence of monocytic vs. granulocytic MDSCs and plasmocytoid vs. conventional dendritic cells (DCs) was present in mammary tumors of IL‐33‐treated mice. Intratumoral NKp46⁺NKG2D⁺ and NKp46⁺FasL⁺ cells were markedly reduced after IL‐33 treatment, while phosphate‐buffered saline‐treated ST2‐deficient mice had increased frequencies of these tumoricidal natural killer (NK) cells compared to untreated wild‐type mice. IL‐33 promoted intratumoral cell proliferation and neovascularization, which was attenuated in the absence of ST2. Tumor‐bearing mice given IL‐33 had increased percentages of splenic MDSCs, Lin⁻Sca‐1⁺ ILCs, IL‐10‐expressing CD11c⁺ DCs and alternatively activated M2 macrophages and higher circulating levels of IL‐10 and IL‐13. A significantly reduced NK cell, but not CD8⁺ T‐cell cytotoxicity in IL‐33‐treated mice was observed and the mammary tumor progression was not affected when CD8⁺ T cells were in vivo depleted. We show a previously unrecognized role for IL‐33 in promoting breast cancer progression through increased intratumoral accumulation of immunosuppressive cells and by diminishing innate antitumor immunity. Therefore, IL‐33 may be considered as an important mediator in the regulation of breast cancer progression.

Mesenchymal stem cells (MSCs) are multipotent, self-renewing cells that can be found in almost all postnatal organs and tissues. The main functional characteristics of MSCs are their immunomodulatory ability, capacity for self-renewal, and differentiation into mesodermal tissues. The ability of MSCs to differentiate into several cell types, including muscle, brain, vascular, skin, cartilage, and bone cells, makes them attractive as therapeutic agents for a number of diseases including complications of diabetes mellitus. We review here the potential of MSCs as new therapeutic agents in the treatment of diabetic cardiomyopathy, diabetic nephropathy, diabetic polyneuropathy, diabetic retinopathy, and diabetic wounds. Also, in this review we discuss the current limitations for MSCs therapy in humans.