Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue
Ballak, Dov B. ; Li, Suzhao ; Cavalli, Giulio ; Stahl, Jonathan L. ; Tengesdal, Isak W. ; Diepen, Janna A. van; Klück, Viola ; Swartzwelter, Benjamin ; Azam, Tania ; Tack, Cees J. ; Stienstra, Rinke ; Mandrup-Poulsen, Thomas ; Seals, Douglas R. ; Dinarello, Charles A. - \ 2018
Journal of Biological Chemistry 293 (2018)37. - ISSN 0021-9258 - p. 14224 - 14236.
Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control.Transgenic mice expressing human interleukin 37 (IL-37),an anti-inflammatory cytokine of the IL-1 family,are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 ug/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets.The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1β in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pM IL-37 reduced spontaneous release of TNF and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.
IL-37 expression reduces lean body mass in mice by reducing food intake
Kuipers, Eline N. ; Dam, Andrea D. van; Ballak, Dov B. ; Wit, Ellemiek A. de; Dinarello, Charles A. ; Stienstra, Rinke ; Diepen, Janna A. van; Rensen, Patrick C.N. ; Boon, Mariëtte R. - \ 2018
International Journal of Molecular Sciences 19 (2018)8. - ISSN 1661-6596
Energy metabolism - Food intake - High fat diet - IL-37
The human cytokine interleukin (IL)-37 is an anti-inflammatory member of the IL-1 family of cytokines. Transgenic expression of IL-37 in mice protects them from diet-induced obesity and associated metabolic complications including dyslipidemia, inflammation and insulin resistance. The precise mechanism of action leading to these beneficial metabolic effects is not entirely known. Therefore, we aimed to assess in detail the effect of transgenic IL-37 expression on energy balance, including food intake and energy expenditure. Feeding homozygous IL-37 transgenic mice and wild-type (WT) control mice a high-fat diet (HFD; 45% kcal palm fat) for 6 weeks showed that IL-37 reduced body weight related to a marked decrease in food intake. Subsequent mechanistic studies in mice with heterozygous IL-37 expression versus WT littermates, fed the HFD for 18 weeks, confirmed that IL-37 reduces food intake, which led to a decrease in lean body mass, but did not reduce fat mass and plasma lipid levels or alterations in energy expenditure independent of lean body mass. Taken together, this suggests that IL-37 reduces lean body mass by reducing food intake.
The effects of selective hematopoietic expression of human IL-37 on systemic inflammation and atherosclerosis in LDLr-deficient mice
Hoeke, Geerte ; Khedoe, P.P.S.J. ; Diepen, Janna A. Van; Pike-Overzet, Karin ; Ven, Britt van de; Vazirpanah, Nadia ; Mol, Isabel ; Hiemstra, Pieter S. ; Staal, Frank J.T. ; Stienstra, Rinke ; Netea, Mihai G. ; Dinarello, Charles A. ; Rensen, Patrick C.N. ; Berbée, Jimmy F.P. - \ 2017
International Journal of Molecular Sciences 18 (2017)8. - ISSN 1661-6596
Atherosclerosis - Hyperlipidemia - Inflammation - Interleukin-37
The human cytokine interleukin (IL)-37 has potent anti-inflammatory capacities, and hematopoietic cell-specific transgenic overexpression of IL-37 in mice protects against septic shock and colitis. In the present study we investigated the effect of hematopoietic expression of IL-37 on atherosclerosis development under low-grade inflammatory conditions. Low-density lipoprotein receptor (LDLr)-deficient mice were lethally irradiated and transplanted with bone marrow from IL-37-transgenic or control wild-type mice and fed a Western-type diet (WTD; 1% cholesterol) for eight weeks. Metabolic and inflammatory parameters were monitored and atherosclerosis was assessed in the aortic valve area. Hematopoietic IL-37 expression did not influence body weight, food intake and plasma cholesterol levels during the study. Plasma soluble E-selectin levels were increased with WTD-feeding as compared to chow-feeding, but were not influenced by IL-37 expression. IL-37 expression reduced the inflammatory state as indicated by reduced white blood cell counts and by reduced basal and lipopolysaccharide-induced cytokine response by peritoneal macrophages ex vivo. IL-37 expression did not influence the atherosclerotic lesion area. Lesion composition was marginally affected. Smooth muscle cell content was decreased, but macrophage and collagen content were not different. We conclude that under low-grade inflammatory conditions, hematopoietic IL-37 expression reduces the inflammatory state, but does not influence atherosclerosis development in hyperlipidemic LDLr-deficient mice.
Understanding human immune function using the resources from the Human Functional Genomics Project
Netea, Mihai G. ; Joosten, Leo A.B. ; Li, Yang ; Kumar, Vinod ; Oosting, Marije ; Smeekens, Sanne ; Jaeger, Martin ; Horst, Rob Ter; Schirmer, Melanie ; Vlamakis, Hera ; Notebaart, Richard ; Pavelka, Norman ; Aguirre-Gamboa, Raul Raul ; Swertz, Morris A. ; Tunjungputri, Rahajeng N. ; De Heijden, Wouter Van; Franzosa, Eric A. ; Ng, Aylwin ; Graham, Daniel ; Lassen, Kara ; Schraa, Kiki ; Netea-Maier, Romana ; Smit, Jan ; Mast, Quirijn De; De Veerdonk, Frank Van; Kullberg, Bart Jan ; Tack, Cees ; De Munckhof, Inge Van; Rutten, Joost ; Graaf, Jacqueline Van Der; Franke, Lude ; Hofker, Marten ; Jonkers, Iris ; Platteel, Mathieu ; Maatman, Astrid ; Fu, Jingyuan ; Zhernakova, Alexandra ; Meer, Jos W.M. Van Der; Dinarello, Charles A. ; Ven, Andre Van Der; Huttenhouwer, Curtis ; Koenen, Hans ; Joosten, Irma ; Xavier, Ramnik J. ; Wijmenga, Cisca - \ 2016
Nature Medicine 22 (2016)8. - ISSN 1078-8956 - p. 831 - 833.
Host and Environmental Factors Influencing Individual Human Cytokine Responses
Horst, Rob ter; Jaeger, Martin ; Smeekens, Sanne P. ; Oosting, Marije ; Swertz, Morris A. ; Li, Yang ; Kumar, Vinod ; Diavatopoulos, Dimitri A. ; Jansen, Anne F.M. ; Lemmers, Heidi ; Toenhake-Dijkstra, Helga ; Herwaarden, Antonius E. van; Janssen, Matthijs ; Molen, Renate G. van der; Joosten, Irma ; Sweep, Fred C.G.J. ; Smit, Johannes W. ; Netea-Maier, Romana T. ; Koenders, Mieke M.J.F. ; Xavier, Ramnik J. ; Meer, Jos W.M. van der; Dinarello, Charles A. ; Pavelka, Norman ; Wijmenga, Cisca ; Notebaart, Richard A. ; Joosten, Leo A.B. ; Netea, Mihai G. - \ 2016
Cell 167 (2016)4. - ISSN 0092-8674 - p. 1111 - 1124.e13.
age - alpha-1-antitrypsin - cytokines - environment - gender - genetics - host - microbiome - season - vitamin D
Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies. PaperClip
Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
Arts, Rob J.W. ; Novakovic, Boris ; Horst, Rob ter; Carvalho, Agostinho ; Bekkering, Siroon ; Lachmandas, Ekta ; Rodrigues, Fernando ; Silvestre, Ricardo ; Cheng, Shih Chin ; Wang, Shuang Yin ; Habibi, Ehsan ; Gonçalves, Luís G. ; Mesquita, Inês ; Cunha, Cristina ; Laarhoven, Arjan van; Veerdonk, Frank L. van de; Williams, David L. ; Meer, Jos W.M. van der; Logie, Colin ; O'Neill, Luke A. ; Dinarello, Charles A. ; Riksen, Niels P. ; Crevel, Reinout van; Clish, Clary ; Notebaart, Richard A. ; Joosten, Leo A.B. ; Stunnenberg, Hendrik G. ; Xavier, Ramnik J. ; Netea, Mihai G. - \ 2016
Cell Metabolism 24 (2016)6. - ISSN 1550-4131 - p. 807 - 819.
cholesterol metabolism - epigenetics - glutamine metabolism - glycolysis - trained immunity
Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.
Activation of proteinase 3 contributes to nonalcoholic fatty liver disease and insulin resistance
Toonen, Erik J.M. ; Mirea, Andreea Manuela ; Tack, Cees J. ; Stienstra, Rinke ; Ballak, Dov B. ; Diepen, Janna A. van; Hijmans, Anneke ; Chavakis, Triantafyllos ; Dokter, Wim H. ; Pham, Christine Tn ; Netea, Mihai G. ; Dinarello, Charles A. ; Joosten, Leo A.B. - \ 2016
Molecular Medicine 22 (2016). - ISSN 1076-1551 - p. 202 - 214.
Activation of inflammatory pathways is known to accompany development of obesity-induced nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive proinflammatory mediators interleukin (IL)-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In this study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human α-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin-resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3-deficient mice showed strongly reduced levels of lipids in the liver after being fed a high-fat diet. Moreover, these mice were resistant to high–fat–diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1–/– mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with α-1 antitrypsin during the last 10 d of a 16-wk high-fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.
IL-1 family members in the pathogenesis and treatment of metabolic disease : Focus on adipose tissue inflammation and insulin resistance
Ballak, D.B. ; Stienstra, Rinke ; Tack, C.J. ; Dinarello, C.A. ; Diepen, J.A. van - \ 2015
Cytokine 75 (2015)2. - ISSN 1043-4666 - p. 280 - 290.
Adipose tissue - Inflammation - Insulin resistance - Interleukin-1 family - Obesity
Obesity is characterized by a chronic, low-grade inflammation that contributes to the development of insulin resistance and type 2 diabetes. Cytokines and chemokines produced by immunocompetent cells influence local as well as systemic inflammation and are therefore critical contributors to the pathogenesis of type 2 diabetes. Hence, cytokines that modulate inflammatory responses are emerging as potential targets for intervention and treatment of the metabolic consequences of obesity. The interleukin-1 (IL-1) family of cytokines and receptors are key mediators of innate inflammatory responses and exhibit both pro- and anti-inflammatory functions. During the last decades, mechanistic insights into how the IL-1 family affects the initiation and progression of obesity-induced insulin resistance have increased significantly. Here, we review the current knowledge and understanding, with emphasis on the therapeutic potential of individual members of the IL-1 family of cytokines for improving insulin sensitivity in patients with diabetes.