IL-33 is a chemoattractant for human Th2 cells

IL-33 is a novel cytokine of the IL-1 family and mediates its biological effect via the receptor ST2, which is selectively expressed on Th2 cells but not Th1 cells. IL-33 drives production of Th2-associated cytokines including IL-5 and IL-13 and thereby promotes defense and pathology in mucosal organs. Cell locomotion is crucial to the induction of an effective immune response. We report here the chemoattraction of Th2 cells by IL-33. Recombinant IL-33 increased the proportion of human Th2 cells, but not Th1 cells, in polarized morphology in vitro and stimulated their subsequent invasion into collagen gels in an IL-33 concentration-dependent manner. Injection of recombinant IL-33 into the footpad of ST2(-/-) mice which had been adoptively transferred with polarized Th2 cells, led to local accumulation of the transferred Th2 cells. These data therefore demonstrate that IL-33 is a selective Th2 chemoattractant associated with the pro-inflammatory property of this novel cytokine.     

IL-33 signalling in liver immune cells enhances drug-induced liver injury and inflammation

Objective and design

The aim of this study was to investigate the contribution of IL-33/ST2 axis in the onset and progression of acute liver injury using a mice model of drug-induced liver injury (DILI).

Material and treatments

DILI was induced by overdose administration of acetaminophen (APAP) by oral gavage in wild-type BALB/c, ST2-deficient mice and in different bone marrow chimeras. Neutrophils were depleted by anti-Ly6G and macrophages with clodronate liposomes (CLL).

Methods

Blood and liver were collected for biochemical, immunologic and genetic analyses. Mice were imaged by confocal intravital microscopy and liver non-parenchymal cells and hepatocytes were isolated for flow cytometry, genetic and immunofluorescence studies.

Results

Acetaminophen overdose caused a massive necrosis and accumulation of immune cells within the liver, concomitantly with IL-33 and chemokine release. Liver non-parenchymal cells were the major sensors for IL-33, and amongst them, neutrophils were the major players in amplification of the inflammatory response triggered by IL-33/ST2 signalling pathway.

Conclusion

Blockage of IL-33/ST2 axis reduces APAP-mediated organ injury by dampening liver chemokine release and activation of resident and infiltrating liver non-parenchymal cells.

     

Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family

Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8⁺ T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells.     

T1/ST2 promotes T helper 2 cell activation and polyfunctionality in bronchopulmonary mycosis

Interleukin (IL)-33 enhances T helper (Th)2 immunity via its receptor T1/ST2. Infection with the yeast-like pathogen Cryptococcus neoformans is usually controlled by a Th1-mediated immune response. The mechanisms responsible for nonprotective Th2 immunity leading to allergic inflammation in pulmonary cryptococcosis are still not fully understood. Using a murine pulmonary model of C. neoformans infection, we report that T1/ST2 expression correlates with the intensity of Th2 activation, as demonstrated by the expression of CD25 and CD44 and downregulation of CD62L. Antigen-specific T1/ST2⁺ Th cells are the primary source of the Th2 cytokines IL-5 and IL-13 as compared with wild-type T1/ST2⁻ Th cells or Th cells from T1/ST2^−/− mice. In addition, T1/ST2⁺ Th cells almost exclusively contain bi- and trifunctional Th2 cytokine-producing Th cells compared with T1/ST2⁻ Th cells or Th cells from T1/ST2^−/− mice. Finally, T1/ST2-driven Th2 development resulted in defective pulmonary fungal control. These data demonstrate that T1/ST2 directs Th2 cell activation and polyfunctionality in allergic bronchopulmonary mycosis.     

IL-33/ST2 as a potential target for tumor immunotherapy

IL-33, a member of the IL-1 family, was initially reported to be expressed constitutively in the nucleus of tissue-lining and structural cells. However, upon tissue damage or injury, IL-33 can be released quickly to bind with its cognate receptor ST2 in response to wound healing and inflammation and act as a DAMP. As a key regulator of Th2 responses, IL-33/ST2 signal is primarily associated with immunity and immune-related disorders. In recent years, IL-33/ST2 signaling pathway has been reported to promote the development of cancer and remodel the tumor microenvironment by expanding immune suppressive cells such as myeloid-derived suppressor cells or regulatory T cells. However, its role remains controversial in some tumor settings. IL-33 could also promote effective infiltration of immune cells such as CD8⁺ T and NK cells, which act as antitumor. These dual effects may limit the clinical application to target this cytokine axis. Therefore, more comprehensive exploration and deeper understanding of IL-33 are required. In this review, we summarized the IL-33/ST2 axis versatile roles in the tumor microenvironment with a focus on the IL-33-target immune cells and downstream signaling pathways. We also discuss how the IL-33/ST2 axis could be used as a potential therapeutic target for cancer immunotherapy.     

IL-33/s-ST2 ratio,systemic symptoms,and basophil activation in Pru p 3-sensitized allergic patients

Background

Although IL-33/ST2 axis is involved in the development of allergic diseases, its contribution in food allergy is still unknown.

Methods

In this study, we assessed the serum levels of IL-33 and its s-ST2 receptor in 53 control patients (without allergic diseases), 47 peach (Pru p 3)-sensitized allergic patients (SAP), and in 68 non-Pru p 3-SAP. Basophil activation test (BAT) was used to assess the basophil activation due to allergen exposure before and after the addition of s-ST2 to the blood samples from 5 Pru p 3-SAP.

Results

IL-33 levels in Pru p 3-SAP were higher than in non-Pru p 3-SAP and in normal controls. Lower s-ST2 levels were found in Pru p 3-SAP than in non-Pru p 3-SAP. IL-33/s-ST2 ratio was higher in Pru p 3-SAP than in both non-Pru p 3-SAP and controls. Higher IL-33/s-ST2 ratio was observed in Pru p 3-SAP with severe than in those with mild systemic symptoms. BAT analysis in Pru p 3-SAP showed a decrease in basophil activation due to Pru p 3 exposure after the addition of s-ST2 to the blood samples.

Conclusions

An imbalance in the baseline levels of IL-33/ST2 pathway is present in Pru p 3-SAP. The measurement of this pathway might be helpful to detect patients at a higher risk of developing severe systemic symptoms.

     

Effects of High-Dose Dexamethasone on Regulating Interleukin-22 Production and Correcting Th1 and Th22 Polarization in Immune Thrombocytopenia

Background

T-cell dysregulation and T-cell-related cytokine abnormalities are involved in the pathogenesis of immune thrombocytopenia (ITP). One of our previous studies showed that elevated IL-22 correlated to Th1 and Th22 cells plays an important role in the immunopathogenesis of ITP. In this study, we aimed to investigate the effects of high-dose dexamethasone (HD-DXM) on IL-22 production and on the IL-22-producing T-cell subsets in ITP patients.

Methods

IL-22 plasma levels and the percentages of Th1, Th17, and Th22 cells were determined by enzyme-linked immunosorbent assay and flow cytometry in 25 ITP patients receiving DXM 40?mg/day for 4 consecutive days.

Results

Plasma IL-22 concentrations and the percentages of Th1 and Th22 cells were significantly increased in pre-therapy patients relative to controls (P?Conclusion These results suggest that HD-DXM may regulate the production of IL-22 in ITP, possibly by correcting Th1 and Th22 polarization.     

Polarized Th2 like cells, in the absence of Th0 cells, are responsible for lymphocyte produced IL-4 in high IgE-producer schistosomiasis patients

Background  

Human resistance to re-infection with S. mansoni is correlated with high levels of anti-soluble adult worm antigens (SWAP) IgE. Although it has been shown that IL-4 and IL-5 are crucial in establishing IgE responses in vitro, the active in vivo production of these cytokines by T cells, and the degree of polarization of Th2 vs. Th0 in human schistosomiasis is not known. To address this question, we determined the frequency of IL-4 and IFN-γ or IL-5 and IL-2 producing lymphocytes from schistosomiasis patients with high or low levels of IgE anti-SWAP.     

IL‐33 Receptor (ST2) Signalling is Important for Regulation of Th2‐Mediated Airway Inflammation in a Murine Model of Acute Respiratory Syncytial Virus Infection

T1/ST2, an orphan receptor with homology with the interleukin (IL)‐1 receptor family, is the ligand‐binding component of the receptor for the cytokine IL‐33, a newly identified cytokine known to amplify the Th2 cell‐dominant immune responses. The function of IL‐33/ST2 signalling during respiratory syncytial virus (RSV) infection is not fully known. In this study, following intranasal infection with RSV, BALB/c mice showed a marked increase in the production of IL‐33, with an elevated expression of ST2 mRNA as well as a massive infiltration of CD45⁺ST2⁺ cells in the lungs, suggesting that during the early phase of RSV infection, IL‐33 target cells which express ST2 on cell surface, may play a critical role for the development of RSV‐induced airway inflammation. Indeed, blocking ST2 signalling using anti‐ST2 monoclonal antibody diminished not only RSV‐induced eosinophil recruitment, but also the amounts of Th2‐associated cytokines, particularly IL‐13, and Th17‐type cytokine IL‐17A in the lungs of infected mice. However, anti‐ST2 antibody treatment did not affect the production of Th1‐type cytokine IFN‐γ as well as pulmonary viral growth and clearance. These results indicate that IL‐33/ST2 signalling is involved in RSV‐induced, Th2‐associated airway inflammation but not protective immunity.     

Signaling through the T1/ST2 molecule is not necessary for Th2 differentiation but is important for the regulation of type 1 responses in nonhealing Leishmania major infection

T1/ST2 is a stable cell surface marker selectively expressed on type 2 T helper (Th2) effector cells. Since nonhealing Leishmania major infections in susceptible BALB/c mice have been ascribed to a polarized Th2 response, we used an anti-T1/ST2 monoclonal antibody (MAb) or a T1-Fc fusion protein to investigate the role of CD4+ T1/ST2(+) Th2 cells in experimental leishmaniasis. We show that interfering with T1/ST2 signaling had no effect on lesion development or parasite replication; however, it induced a significantly higher type 1 response and an enhanced capacity of CD4+ T cells to respond to interleukin 12 (IL-12). Surprisingly, even in the presence of an elevated Th1 response, the production of antigen-specific type 2 cytokines was not altered in the group of mice treated with the anti-T1/ST2 MAb or the T1-Fc fusion protein. To characterize further this Th2 response, we assessed the cytokine profile of CD4+ T cells and found that interfering with T1/ST2 signaling did not alter the cytokine profile of CD4+ T1/ST2(+) T cells. These results show that T1/ST2 signaling is not necessary for the differentiation of naive CD4+ T cells into antigen-specific CD4+ T1/ST2(+) Th2 cells. In addition to CD4+ T1/ST2(+) T cells, we detected another subpopulation of CD4+ Th2 cells, negative for the expression of T1/ST2, that could differentiate in vivo in response to L. major infection. Taken together, our results suggest that CD4+ T1/ST2(+) Th2 cells but not CD4+ T1/ST2(-) Th2 cells can downregulate the Th1 response during the course of a nonhealing L. major infection through a mechanism that is independent of IL-4 or IL-10.     

IL-33 attenuates EAE by suppressing IL-17 and IFN-γ production and inducing alternatively activated macrophages

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.     

Interleukin-25 reduces Th17 cells and inflammatory responses in human peripheral blood mononuclear cells

Background

The absence of interleukin-25 (IL-25) favors the induction of Th1 and Th17 immune responses in mice. Th1 immune responses have been associated with the pathology of atherosclerosis, a lipid and inflammation driven disease of the arterial wall.

Th22, but not Th17 Might be a Good Index to Predict the Tissue Involvement of Systemic Lupus Erythematosus

Purpose

T-helper (Th) cells abnormalities are considered to be associated with the pathogenesis of Systemic lupus erythematosus (SLE). Recently, The Th22 cells have been identified and implicated in the pathogenesis of autoimmune diseases such as Rheumatoid arthritis (RA), although therir role in Systemic lupus erythematosus (SLE) remains unclear. The present study intends to investigate their roles in SLE.

Methods

Clinical data were collected in 65 SLE patients and 30 healthy controls. The patients were divided into active and inactive groups. CD4⁺IFN-γ^?IL-17^?IL-22⁺Tcells (Th22 cells),CD4⁺ IFN-γ^?IL-22^?IL-17⁺T cells (Th17 cells),and CD4⁺ IFN-γ⁺ (Th1 cells) were assayed by flow cytometry. Serum interleukin-22 (IL-22) and IL-17 levels were measured by enzyme-linked immunosorbent assay.

Results

The main observation focused on increased Th22 cells in patients with sole lupus skin disease and decreased Th22 cells in patients with sole lupus nephritis. Likewise, concentrations of serum IL-22 were increased in patients with sole lupus skin disease, and decreased in patients with sole lupus nephritis. Additionally, there was a positive correlation between the percentage of Th22 cells and IL-22 production. The percentage of Th17 cells or concentration of serum IL-17 correlated positively with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

Conclusion

Th22 seems to be a more significant index to predict the tissue involvement of SLE than Th17, although Th17 may play a role in the activity of SLE.