IL-21 promotes myocardial ischaemia/reperfusion injury through the modulation of neutrophil infiltration.

BACKGROUND AND PURPOSE: The immune system plays an important role in driving the acute inflammatory response following myocardial ischaemia/reperfusion injury (MIRI). IL-21 is a pleiotropic cytokine with multiple immunomodulatory effects, but its role in MIRI is not known. EXPERIMENTAL APPROACH: Myocardial injury, neutrophil infiltration and the expression of neutrophil chemokines KC (CXCL1) and MIP-2 (CXCL2) were studied in a mouse model of MIRI. Effects of IL-21 on the expression of KC and MIP-2 in neonatal mouse cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were determined by real-time PCR and ELISA. The signalling mechanisms underlying these effects were explored by western blot analysis. KEY RESULTS: IL-21 was elevated within the acute phase of murine MIRI. Neutralization of IL-21 attenuated myocardial injury, as illustrated by reduced infarct size, decreased cardiac troponin T levels and improved cardiac function, whereas exogenous IL-21 administration exerted opposite effects. IL-21 increased the infiltration of neutrophils and increased the expression of KC and MIP-2 in myocardial tissue following MIRI. Moreover, neutrophil depletion attenuated the IL-21-induced myocardial injury. Mechanistically, IL-21 increased the production of KC and MIP-2 in neonatal CMs and CFs, and enhanced neutrophil migration, as revealed by the migration assay. Furthermore, we demonstrated that this IL-21-mediated increase in chemokine expression involved the activation of Akt/NF-κB signalling in CMs and p38 MAPK/NF-κB signalling in CFs. CONCLUSIONS AND IMPLICATIONS: Our data provide novel evidence that IL-21 plays a pathogenic role in MIRI, most likely by promoting cardiac neutrophil infiltration. Therefore, targeting IL-21 may have therapeutic potential as a treatment for MIRI. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

[Roles of interleukin-21 and its receptor in autoimmune diseases].

Interleukin-21 (IL-21) is a new member of the interleukin-2 family. It is mainly synthesized and secreted by the activated of CD4(+) T cells and natural killer T cells. IL-21 receptor (IL-21R) is mainly expressed in T cells, B cells, and natural killer (NK) cells. After binding to its receptor, IL-21 can regulate the activation and proliferation of T cells, B cells, and NK cells through activating JAKs-STATs signaling pathways. As a new immunoregulatory factor, IL-21 and its receptor play important roles in the development and progression of various autoimmune diseases. Regulation of the expression levels of IL-21 and IL-21R and blocking of their signal transduction pathways with blockers may be new treatment options for autoimmune diseases.

IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection.

Influenza A virus (IAV) infection of the respiratory tract elicits a robust immune response, which is required for efficient virus clearance but at the same time can contribute to lung damage and enhanced morbidity. IL-21 is a member of the type I cytokine family and has many different immune-modulatory functions during acute and chronic virus infections, although its role in IAV infection has not been fully evaluated. In this report we evaluated the contributions of IL-21/IL-21 receptor (IL-21R) signaling to host defense in a mouse model of primary IAV infection using IL-21R knock out (KO) mice. We found that lack of IL-21R signaling had no significant impact on virus clearance, adaptive T cell responses, or myeloid cell accumulations in the respiratory tract. However, a subset of inflammatory cytokines were elevated in the bronchoalveolar lavage fluid of IL-21R KO mice, including IL-17. Although there was only a small increase in Th17 cells in the lungs of IL-21R KO mice, we observed a dramatic increase in gamma delta (γδ) T cells capable of producing IL-17 both after IAV infection and at steady state in the respiratory tract. Finally, we found that IL-21R signaling suppressed the accumulation of IL-17+ γδ T cells in the respiratory tract intrinsically. Thus, our study reveals a previously unrecognized role of IL-21R signaling in regulating IL-17 production by γδ T cells.

Exploring the IL-21-STAT3 axis as therapeutic target for Sézary syndrome.

Sézary syndrome is an aggressive cutaneous T-cell lymphoma. The malignant cells (Sézary cells) are present in skin, lymph nodes, and blood, and express constitutively activated signal transducer and activator of transcription (STAT)3. STAT3 can be activated by IL-21 in vitro and the IL-21 gene itself is a STAT3 target gene, thereby creating an autocrine positive feedback loop that might serve as a therapeutic target. Sézary cells underwent apoptosis when incubated with Stattic, a selective STAT3 inhibitor. STAT3 activation in Sézary cells did not affect expression of the supposed anti-apoptotic STAT3 target genes BCL2, BCL-xL, and SURVIVIN, whereas expression of (proto)oncogenes miR-21, TWIST1, MYC, and PIM1 was significantly increased. CD3/CD28-mediated activation of Sézary cells induced IL-21 expression, accompanied by STAT3 activation and increased proliferation. Blocking IL-21 in CD3/CD28-activated cells had no effects, whereas Stattic abrogated IL-21 expression and cell proliferation. Thus, specific inhibition of STAT3 is highly efficient in the induction of apoptosis of Sézary cells, likely mediated via the regulation of (proto)oncogenes. In contrast, blocking IL-21 alone seems insufficient to affect STAT3 activation, cell proliferation, or apoptosis. These data provide further insights into the pathogenic role of STAT3 in Sézary syndrome and strengthen the notion that STAT3 represents a promising therapeutic target in this disease.

Cutting edge: CD40-CD40 ligand pathway plays a critical CD8-intrinsic and -extrinsic role during rescue of exhausted CD8 T cells.

CD8 exhaustion mediated by an inhibitory programmed death-1-programmed death ligand-1 (PD-L1) pathway occurs in several chronic infections, including toxoplasmosis. Although blockade of the programmed death-1-PD-L1 pathway revives this response, the role of costimulatory receptors involved in this rescue has not been ascertained in any model of CD8 exhaustion. This report demonstrates that one such costimulatory pathway, CD40-CD40L, plays a critical role during rescue of exhausted CD8 T cells. Blockade of this pathway abrogates the ameliorative effects of anti-PD-L1 treatment on CD8 T cells. Additionally, we demonstrate in an infectious disease model that CD8-intrinsic CD40 signaling is important for optimal CD8 polyfunctionality, proliferation, T-bet upregulation, and IL-21 signaling, albeit in the context of CD8 rescue. The critical role of CD40 during the rescue of exhausted CD8 T cells may provide a rational basis for designing novel therapeutic vaccination approaches.

IL-21 receptor is critical for the development of memory B cell responses.

Development of long-term humoral immunity, characterized by the formation of long-lived plasma cells (PCs) in the bone marrow and memory B cells, is a critical component of protective immunity to pathogens, and as such it is the major goal of vaccination. However, the mechanisms involved in the generation of long-term humoral immunity remain poorly understood. In this study, we used IL-21R-deficient (IL-21R.KO) mice to examine the role of the IL-21 pathway in the development of the B cell memory response. Primary IgG serum Ab responses to the T cell-dependent Ag 4-hydroxy-3-nitrophenylacetyl (NP) hapten conjugated to chicken γ globulin were delayed in IL-21R.KO mice, but reached normal titers within 3 to 4 wk of immunization. IL-21R.KO mice formed germinal centers and generated normal numbers of PCs in their bone marrow. Additionally, memory B cell formation was similar in wild-type and IL-21R.KO mice. However, NP-specific memory B cells and PCs failed to expand following secondary immunization of IL-21R.KO mice, and consequently, secondary IgG Ab responses to NP hapten conjugated to chicken γ globulin were significantly impaired. These results identify the IL-21 pathway as a critical component of the memory B cell response.

Interleukin-21 (IL-21)-mediated pathways in T cell-mediated disease.

Interleukin-21 (IL-21) is produced mostly by activated CD4+ T cells and controls the differentiation and functional activity of effector T helper cells, counteracts the suppressive effects of regulatory T cells, and stimulates non-immune cells to make inflammatory mediators. IL-21-driven tissue damage has been demonstrated in a number of organs, such as the gut, pancreas, and brain. Therefore new treatment modalities to neutralise IL-21 in vivo would be a valuable addition to the therapeutic armamentarium to combat immune-mediated inflammation. Here we describe the emerging role of IL-21 in the initiation and progress of the tissue-damaging inflammatory response in immune-mediated pathologies.

Interleukin 21: a cytokine/cytokine receptor system that has come of age.

Interleukin-21 (IL-21) and its receptor represent the sixth cytokine system whose actions were recognized to require the common cytokine receptor gamma chain. IL-21 is produced by activated CD4+ T cells, natural killer T cells, and follicular T helper cells and has actions on a range of lymphohematopoietic lineages. Among its many effects, IL-21 serves a critical role for immunoglobulin production and terminal B cell differentiation, acts as a T cell comitogen and can drive the expansion of CD8+ T cells, can negatively regulate dendritic cell function and plays an essential role in the differentiation of Th17 cells. Importantly, IL-21 is implicated in the pathogenesis of autoimmunity and exhibits potent actions as an antitumor agent. The ability to regulate and manipulate the actions of IL-21, therefore, has important implications for immunoregulation and the therapy of human disease.

Interleukin-21: a new modulator of immunity, infection, and cancer.

Interleukin-21 is the most recently discovered member of the type-I cytokine family. Structurally, IL-21 shows homology to IL-2, IL-4, and IL-15 proteins. IL-21 shares the common gamma-chain with the other three cytokines but, in addition, binds to a unique IL-21Ralpha chain, and activates the JAK/STAT pathway. IL-21 is mainly produced by activated T-cells but targets a broad range of lymphoid and myeloid cells of the immune system and therefore is able to regulate innate and acquired immune responses. This review intends to give the reader an overview of the recent findings concerning the biology of IL-21 and its physiological role in immunity, infection, and cancer.