Immune reactivity plays an important role in obesity-associated metabolic disorders. We investigated immunometabolic phenotype of C57Bl/6 and BALB/c mice, prototypical Th1 and Th2-type strains, fed ...chow or high-fat diet (HFD) for 24 weeks. In comparison to C57Bl/6 mice, chow-fed BALB/c mice had higher body weight and weight gain, lower glycemia, more pronounced liver steatosis, but less inflammation and collagen deposition in liver. In response to HFD C57Bl/6 mice exhibited higher weight gain, higher glycemia, HbA1c and liver glycogen content, increased amount of visceral adipose tissue (VAT) and number of VAT associated CD3+CXCR3+ T cells, CD11c+ dendritic cells (DCs) and F4/80+ macrophages than BALB/c mice. More numerous CD3+ and CD8+ T lymphocytes, myeloid DCs, proinflammatory macrophages (F4/80+CD11b+CD11+ and F4/80+IL-1β+) and CD11b+Ly6Chigh monocytes and higher levels of proinflammatory IL-6, TNF-α and IFN-γ were present in liver in HFD-fed C57Bl/6 mice compared with diet-matched BALB/c mice. As opposed to C57Bl/6 mice, HFD induced marked liver steatosis and upregulated the hepatic LXRα and PPARγ genes in BALB/c mice. C57Bl/6 mice fed HFD developed liver fibrosis and increased hepatic procollagen and TGF-β mRNA expression, and IL-33, IL-13 and TGF-β levels in liver homogenates, while BALB/c mice fed HFD had scarce collagen deposition in liver. The obtained results suggest inherent immunometabolic differences in C57Bl/6 and BALB/c mice. Moreover, HFD Th1-type mice on high fat diet regimen are more susceptible to adiposity, liver inflammation and fibrosis, while Th2-type mice to liver steatosis, which is associated with differential immune cell composition in metabolic tissues. Strain-dependent differences in immunometabolic phenotype may be relevant for studies of obesity-associated metabolic diseases in humans.
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.
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.
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This study employed a breast cancer cell line to investigate the role of interleukin‐33 in cancer progression. They found more IL‐33 in the cells as the disease advanced, and they showed that administring IL‐33 to mice accelerated growth and metastasis. The increased levels of IL‐33 sped cancer progression both by hindering antitumor immunity and by encouraging angiogenesis. Understanding the effects of IL‐33 on cancer suggests possible avenues for tumor immunotherapy.
•The therapeutic potential of frog skin peptides as anti-infective agents has not been realized.•Cytotoxic peptides show potential as anti-cancer and anti-viral agents.•Certain peptides stimulate ...production of pro- and anti-inflammatory cytokines.•Such peptides may act as anti-inflammatory, immunosuppressive, or immunostimulatory agents.•Peptides that stimulate insulin release show potential in Type 2 diabetes therapy.
Frog skin constitutes a rich source of peptides with a wide range of biological properties. These include host-defense peptides with cytotoxic activities against bacteria, fungi, protozoa, viruses, and mammalian cells. Several hundred such peptides from diverse species have been described. Although attention has been focused mainly on antimicrobial activity, the therapeutic potential of frog skin peptides as anti-infective agents remains to be realized and no compound based upon their structures has yet been adopted in clinical practice. Consequently, alternative applications are being explored. Certain naturally occurring frog skin peptides, and analogs with improved therapeutic properties, show selective cytotoxicity against tumor cells and viruses and so have potential for development into anti-cancer and anti-viral agents. Some peptides display complex cytokine-mediated immunomodulatory properties. Effects on the production of both pro-inflammatory and anti-inflammatory cytokines by peritoneal macrophages and peripheral blood mononuclear cells have been observed so that clinical applications as anti-inflammatory, immunosuppressive, and immunostimulatory agents are possible. Several frog skin peptides, first identified on the basis of antimicrobial activity, have been shown to stimulate insulin release both in vitro and in vivo and so show potential as incretin-based therapies for treatment of patients with Type 2 diabetes mellitus. This review assesses the therapeutic possibilities of peptides from frogs belonging to the Ascaphidae, Alytidae, Pipidae, Dicroglossidae, Leptodactylidae, Hylidae, and Ranidae families that complement their potential role as anti-infectives for use against multidrug-resistant microorganisms.
The administration of interleukin 33 and deletion of IL-33 receptor, ST2 molecule, affects the induction of autoimmunity in different experimental models of human autoimmune diseases. The aim of this ...study was to analyze the effect of ST2 deletion on the induction of experimental autoimmune encephalomyelitis (EAE) in resistant BALB/c mice. Mice were immunized with MOG(35-55) peptide or disease was induced by passive transfer of encephalitogenic singenic cells and EAE was clinically and histologically evaluated. Expression of intracellular inflammatory cytokines, markers of activation and chemokine receptors on lymphoid tissue and CNS infiltrating mononuclear cells was analyzed by flow cytometry. We report here that deletion of ST2(-/-) molecule abrogates resistance of BALB/c mice to EAE induction based on clinical and histopathological findings. Brain and spinal cord infiltrates of ST2(-/-) mice had significantly higher number of CD4(+) T lymphocytes containing inflammatory cytokines compared to BALB/c WT mice. Adoptive transfer of ST2(-/-) primed lymphocytes induced clinical signs of the disease in ST2(-/-) as well as in WT mice. MOG(35-55) restimulated ST2(-/-) CD4(+) cells as well as ex vivo analyzed lymph node cells had higher expression of T-bet and IL-17, IFN-γ, TNF-α and GM-CSF in comparison with WT CD4(+) cells. ST2(-/-) mice had higher percentages of CD4(+) cells expressing chemokine receptors important for migration to CNS in comparison with WT CD4(+) cells. Draining lymph nodes of ST2(-/-) mice contained higher percentage of CD11c(+)CD11b(+)CD8(-) cells containing inflammatory cytokines IL-6 and IL-12 with higher expression of activation markers. Transfer of ST2(-/-) but not WT dendritic cells induced EAE in MOG(35-55) immunized WT mice. Our results indicate that ST2 deficiency attenuates inherent resistance of BALB/c mice to EAE induction by enhancing differentiation of proinflammatory antigen presenting cells and consecutive differentiation of encephalitogenic T cells in the draining lymph node rather than affecting their action in the target tissue.
Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, binds to its plasma membrane receptor, heterodimeric complex consisted of membrane-bound ST2L and IL-1R accessory protein, inducing ...NFkB and MAPK activation. IL-33 exists as a nuclear precursor and may act as an alarmin, when it is released after cell damage or as negative regulator of NFκB gene transcription, when acts in an intracrine manner. ST2L is expressed on several immune cells: Th2 lymphocytes, NK, NKT and mast cells and on cells of myeloid lineage: monocytes, dendritic cells and granulocytes. IL-33/ST2 axis can promote both Th1 and Th2 immune responses depending on the type of activated cell and microenvironment and cytokine network in damaged tissue. We previously described and discuss here the important role of IL-33/ST2 axis in experimental models of type 1 diabetes, experimental autoimmune encephalomyelitis, fulminant hepatitis and breast cancer. We found that ST2 deletion enhance the development of T cell-mediated autoimmune disorders, EAE and diabetes mellitus type I. Disease development was accompanied by dominantly Th1/Th17 immune response but also higher IL-33 production, which suggest that IL-33 in receptor independent manner could promote the development of inflammatory autoreactive T cells. IL-33/ST2 axis has protective role in Con A hepatitis. ST2-deficient mice had more severe hepatitis with higher influx of inflammatory cells in liver and dominant Th1/Th17 systemic response. Pretreatment of mice with IL-33 prevented Con A-induced liver damage through prevention of apoptosis of hepatocytes and Th2 amplification. Deletion of IL-33/ST2 axis enhances cytotoxicity of NK cells, production of IFN-γ in these cells and systemic production of IFN-γ, IL-17 and TNF-α, which leads to attenuated tumor growth. IL-33 treatment of tumor-bearing mice suppresses activity of NK cells, dendritic cell maturation and enhances alternative activation of macrophages. In conclusion, we observed that IL-33 has attenuated anti-inflammatory effects in T cell-mediated responses and that both IL-33 and ST2 could be further explored as potential therapeutic targets in treatment of immune-mediated diseases.
Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic ...fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis.
Regulatory T (Treg) cells dampen an exaggerated immune response to viral infections in order to avoid immunopathology. Cytomegaloviruses (CMVs) are herpesviruses usually causing asymptomatic ...infection in immunocompetent hosts and induce strong cellular immunity which provides protection against CMV disease. It remains unclear how these persistent viruses manage to avoid induction of immunopathology not only during the acute infection but also during life-long persistence and virus reactivation. This may be due to numerous viral immunoevasion strategies used to specifically modulate immune responses but also induction of Treg cells by CMV infection. Here we demonstrate that liver Treg cells are strongly induced in mice infected with murine CMV (MCMV). The depletion of Treg cells results in severe hepatitis and liver damage without alterations in the virus load. Moreover, liver Treg cells show a high expression of ST2, a cellular receptor for tissue alarmin IL-33, which is strongly upregulated in the liver of infected mice. We demonstrated that IL-33 signaling is crucial for Treg cell accumulation after MCMV infection and ST2-deficient mice show a more pronounced liver pathology and higher mortality compared to infected control mice. These results illustrate the importance of IL-33 in the suppressive function of liver Treg cells during CMV infection.
Gal-3 has the role in multiple inflammatory pathways. Multiple-hit etiology of primary biliary cholangitis (PBC) and evolving immune response at various stages of the disease includes involvement of ...Gal-3 in PBC pathogenesis. In this study we aimed to clarify the role of Gal-3 in
(
) induced biliary disease. Autoimmune cholangitis was induced in mice by two intra-peritoneal injections of
within 2 weeks. The role of Gal-3 was evaluated by using Lgals3
mice and mice treated with Gal-3 inhibitor. The histological and serological parameters of disease, phenotype of dendritic, NK, NKT, and T cells and inflammasome expression were evaluated. Marked attenuation of the disease in Lgals3
and Gal-3 inhibitor, DAVANAT
, treated mice is manifested by the absence of bile duct damage, granulomas and fibrosis. Liver infiltrates of
infected wild type mice had higher incidence of pro-inflammatory macrophages, dendritic cells, NK, NKT, and T cells. Lgals3 deletion and treatment with Gal-3 inhibitor reduced inflammatory mononuclear cell infiltrate, expression of NLRP3 inflammasome in the liver infiltrates and interleukin-1β (IL-1β) production in the livers of
infected mice.
stimulation of wild type peritoneal macrophages with
caused increased NLRP3 expression, caspase-1 activity and IL-1β production compared with Lgals3
cells. Our data highlight the importance of Gal-3 in promotion of inflammation in
induced PBC by enhancing the activation of NLRP3 inflammasome and production of IL-1β and indicate Gal-3 as possible therapeutical target in autoimmune cholangitis. Galectin-3 appears involved in inflammatory response to gut commensal leading to PBC.
Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune‐mediated acute liver failure. Although it is known that MSCs can ...regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17–producing cells in acute liver injury, is still unknown. By using 2 well‐established murine models of neutrophil and NKT cell–mediated acute liver failure (induced by carbon tetrachloride and α‐galactoceramide), we investigated molecular and cellular mechanisms involved in MSC‐mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3‐dioxygenase (IDO)–dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17–producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10–producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC‐treated mice. MSCs did not significantly alter the total number of IL17‐producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell–conditioned medium (MSC‐CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1‐methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO‐dependent manner may be used as a new therapeutic approach in IL17‐driven liver inflammation. Liver Transplantation 23 1040–1050 2017 AASLD.
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