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Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation

Nature Immunology volume 18, pages 283–292 (2017)Cite this article

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Abstract

The deleterious effect of chronic activation of the IL-1β system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1β in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1β, in a glucose-dependent manner. Subsequently, IL-1β contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1β signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1β and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1β mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium–glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1β and insulin in the regulation of both metabolism and immunity.

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Figure 1: Feeding stimulates intraperitoneal macrophages to produce IL-1β.
Figure 2: Postprandial macrophage-derived IL-1β promotes insulin secretion.
Figure 3: Acute exposure to IL-1β induces insulin secretion without changing sensitivity to insulin.
Figure 4: Systemic IL-1β potentiates glucose-induced insulin secretion via islet IL-1R1.
Figure 5: Expression and activation of InsR in peritoneal macrophages.
Figure 6: Insulin stimulates the secretion of IL-1β by macrophages.
Figure 7: IL-1β shifts glucose uptake to immune cells.

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References

  1. Dinarello, C.A. Multiple biological properties of recombinant human interleukin 1 (β). Immunobiology 172, 301–315 (1986).

    Article  CAS  PubMed  Google Scholar 

  2. Wellen, K.E. & Hotamisligil, G.S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Donath, M.Y., Dalmas, É., Sauter, N.S. & Böni-Schnetzler, M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab. 17, 860–872 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Ehses, J.A., Böni-Schnetzler, M., Faulenbach, M. & Donath, M.Y. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochem. Soc. Trans. 36, 340–342 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Donath, M.Y. & Shoelson, S.E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Stienstra, R. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12, 593–605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Maedler, K. et al. Glucose-induced beta cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Masters, S.L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Stienstra, R. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl. Acad. Sci. USA 108, 15324–15329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ehses, J.A. et al. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc. Natl. Acad. Sci. USA 106, 13998–14003 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Larsen, C.M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. van Asseldonk, E.J. et al. Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 96, 2119–2126 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Cavelti-Weder, C. et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care 35, 1654–1662 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hensen, J., Howard, C.P., Walter, V. & Thuren, T. Impact of interleukin-1β antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab. 39, 524–531 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Sloan-Lancaster, J. et al. Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1β antibody, in patients with type 2 diabetes. Diabetes Care 36, 2239–2246 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gubser, P.M. et al. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Fox, C.J., Hammerman, P.S. & Thompson, C.B. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5, 844–852 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Macintyre, A.N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Freemerman, A.J. et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 289, 7884–7896 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tannahill, G.M. et al. Succinate is an inflammatory signal that induces IL-1(through HIF-1α. Nature 496, 238–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Böni-Schnetzler, M. et al. Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology 150, 5218–5229 (2009).

    Article  PubMed  CAS  Google Scholar 

  28. Benner, C. et al. The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15, 620 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bendtzen, K. et al. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 232, 1545–1547 (1986).

    Article  CAS  PubMed  Google Scholar 

  30. Mandrup-Poulsen, T. et al. Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia 29, 63–67 (1986).

    Article  CAS  PubMed  Google Scholar 

  31. Zawalich, W.S. & Zawalich, K.C. Interleukin 1 is a potent stimulator of islet insulin secretion and phosphoinositide hydrolysis. Am. J. Physiol. 256, E19–E24 (1989).

    CAS  PubMed  Google Scholar 

  32. Donath, M.Y., Böni-Schnetzler, M., Ellingsgaard, H., Halban, P.A. & Ehses, J.A. Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol. Metab. 21, 261–267 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Caumo, A. & Luzi, L. First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am. J. Physiol. Endocrinol. Metab. 287, E371–E385 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Baggio, L.L. & Drucker, D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Van Oostrom, A.J., Sijmonsma, T.P., Rabelink, T.J., Van Asbeck, B.S. & Cabezas, M.C. Postprandial leukocyte increase in healthy subjects. Metabolism 52, 199–202 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Herieka, M. & Erridge, C. High-fat meal induced postprandial inflammation. Mol. Nutr. Food Res. 58, 136–146 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Pétrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).

    Article  PubMed  CAS  Google Scholar 

  38. Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Platell, C., Cooper, D., Papadimitriou, J.M. & Hall, J.C. The omentum. World J. Gasteroenterol. 6, 169–176 (2000).

    Google Scholar 

  40. Shrivastava, P. & Bhatia, M. Essential role of monocytes and macrophages in the progression of acute pancreatitis. World J. Gasteroenterol. 16, 3995–4002 (2010).

    Article  CAS  Google Scholar 

  41. Cani, P.D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Breton, J. et al. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab. 23, 324–334 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Corbett, J.A., Wang, J.L., Sweetland, M.A., Lancaster, J.R. Jr. & McDaniel, M.L. Interleukin 1β induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. J. Clin. Invest. 90, 2384–2391 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hajmrle, C. et al. Interleukin-1 signaling contributes to acute islet compensation. J. Clin. Invest. 1, e86055 (2016).

    Google Scholar 

  46. Greenwood, R.H., Mahler, R.F. & Hales, C.N. Improvement in insulin secretion in diabetes after diazoxide. Lancet 1, 444–447 (1976).

    Article  CAS  PubMed  Google Scholar 

  47. Olefsky, J.M. & Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Mauer, J. et al. Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance. PLoS Genet. 6, e1000938 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Costa Rosa, L.F., Safi, D.A., Cury, Y. & Curi, R. The effect of insulin on macrophage metabolism and function. Cell Biochem. Funct. 14, 33–42 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Ravassard, P. et al. A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion. J. Clin. Invest. 121, 3589–3597 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Horai, R. et al. Production of mice deficient in genes for interleukin (IL)-1α, IL-1β, IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463–1475 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Farley, F.W., Soriano, P., Steffen, L.S. & Dymecki, S.M. Widespread recombinase expression using FLPeR (flipper) mice. Genesis 28, 106–110 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Clausen, B.E., Burkhardt, C., Reith, W., Renkawitz, R. & Förster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Preitner, F. et al. Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J. Clin. Invest. 113, 635–645 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wueest, S. et al. Fas (CD95) expression in myeloid cells promotes obesityinduced muscle insulin resistance. EMBO Mol. Med. 6, 43–56 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Caiazzo, R. et al. Quantitative in vivo islet potency assay in normoglycemic nude mice correlates with primary graft function after clinical transplantation. Transplantation 86, 360–363 (2008).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank R. Sharfmann (Université Paris-Descartes, Institut Cochin, Paris, France) for the human β-cell line ENDOC; technicians M. Borsigova, K. Dembinski and S. Haeuselmann for technical assistance; S. Dimeloe, E. Traunecker and D. Labes for technical advice; G. Bantug for technical and editorial advice; and the Center for Transgenic Models of the University of Basel and D. Klewe-Nebenius for supporting production of the Il1bfl/fl mouse. Supported by the Swiss National Research Foundation (166519 to M.Y.D.) and the European Genomic Institute for Diabetes (ANR-10-LABX-46 to F.P.).

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Author notes

  1. Elise Dalmas, Daniel T Meier, Marianne Böni-Schnetzler and Marc Y Donath: These authors contributed equally to this work.

Authors and Affiliations

  1. and Department of Biomedicine, Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, University of Basel, Basel, Switzerland.,

    Erez Dror, Elise Dalmas, Daniel T Meier, Constanze Thienel, Katharina Timper, Thierry M Nordmann, Shuyang Traub, Friederike Schulze, Marianne Böni-Schnetzler & Marc Y Donath

  2. Deptartment of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, Zurich, Switzerland

    Stephan Wueest, Flurin Item & Daniel Konrad

  3. Inserm, University Lille, Centre Hospitalier Universitaire, Lille, France, and Translational Research for Diabetes, European Genomic Institute for Diabetes, Lille, France

    Julien Thévenet, Francois Pattou & Julie Kerr-Conte

  4. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

    David Vallois & Bernard Thorens

  5. Department of Surgery, Cell Isolation and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland, and University of Geneva School of Medicine, Geneva, Switzerland.,

    Vanessa Lavallard & Thierry Berney

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Contributions

E.Dr., M.B.-S. and M.Y.D. designed the study and wrote the manuscript; E.Dr. performed and analyzed most of the experiments; E.Da, D.T.M. and M.B.-S. performed and analyzed experiments; S.W., F.I. and D.K. performed the clamping; J.T., F.P. and J.K.-C. provided human islets and performed the islet-transplantation experiments; C.T., K.T., T.M.N., S.T., F.S. and D.V. helped with experiments; V.L. and T.B. provided human islets; B.T. provided the Gipr−/−Glp1r−/− mice; M.B.-S. and M.Y.D. supervised the research; and all authors helped with the manuscript.

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Correspondence to Marc Y Donath.

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Competing interests

M.Y.D. is listed as the inventor on a patent filed in 2003 for the use of an IL-1 receptor antagonist for the treatment of or prophylaxis for type 2 diabetes.

Integrated supplementary information

Supplementary Figure 1 Feeding stimulates intraperitoneal macrophages, which are primed by the gut microbiota to produce IL-1β in a glucose-dependent manner.

(a) Representative standard curve (blue) from IL-1β MSD assay including data points of samples (red dots) from refeeding experiments (sera) or from supernatants of cultivated macrophages. (b) Gating strategy and staining: live, single peritoneal cells were stained for CD11b and F4/80 (macrophages) or CD3e (T cells), CD19 (B cells), Siglec-F (eosinophils) and GR-1 (granulocytes). (c) Design of transgenic allele of the EUCOMM ES cell and the generation of Il1bfl/flLyz2-Cre+/- and littermate control mice. (d) Glycosuria (dark blue) in mice injected with the SGLT2 inhibitor canagliflozin (asterisks) compared to placebo treated mice (glucose negative; yellow). (e) Blood glucose levels and (f) circulating insulin levels before (fasted) or after refeeding (refed) in mice treated with or without the SGLT2 inhibitor canagliflozin (n=13 per group). (g) Il1b and (h) Cxcl1 gene expression in omental fat isolated from refed mice pretreated with or without ABX (n=11 per group). (i) Circulating IL-1β levels before (fasted) or after refeeding (refed) in mice treated with or without antibiotics (control; n=11, ABX; n=13). Food intake of mice treated with or without ABX during (j) a 2-hour refeeding experiment and (k) during ABX treatment (one week, n=2 experiments). (l) Number of peritoneal cells isolated from control or 1 week ABX treated mice (n=11 and 10, respectively). *P < 0.0001. Statistical significance (P) was determined by ANOVA. All error bars denote s.e.m.

Supplementary Figure 2 Postprandial macrophage-derived IL-1β promotes insulin secretion.

(a) Blood glucose levels before (fasted) or after refeeding (refed) in WT and Il1b–/– littermate mice (n=12 and 6, respectively). (b) Representative FACS plot of peritoneal macrophage (CD11b+, F4/80+) depletion in WT mice 3 days after injection of 10 ml/kg clodronate or PBS liposomes, gated on live single cells. (c) Blood glucose levels following acute injections of saline or 10 mg/kg IL-1Ra in refed WT mice (n=26 and 23, respectively). *P<0.05, **P < 0.01. Statistical significance (P) was determined by Student's t test and in (a) by ANOVA. All error bars denote s.e.m.

Supplementary Figure 3 Acute exposure to IL-1β induces insulin secretion without changing insulin sensitivity.

(a) Circulating active GLP-1 protein levels in WT mice injected with saline or 1 μg/kg IL-1β. (b) Glucose and (c) insulin levels during i.p. GTT with Gipr-/-/Glp1r-/- double knockout (KO; n=7) or WT (n=8) mice. (d) Insulin tolerance test 18 minutes after an injection of saline (n=5) or 1 μg/kg IL-1β (n=6) in WT mice. (e) Circulating glucose and (f) insulin levels during an i.p. GTT with IRAK4 knockout mice, pretreated with saline or 1 μg/kg IL-1β (n=6). (g-i) Insulin concentrations in culture media of islets isolated from mice (g; left to right: n=9, 13, 9, 12; 3 experiments) and humans (h; left to right: n=44, 9, 34, 15; 8 experiments) and of human ENDOC cells (i; n=9; 3 experiments) pre-incubated with the indicated doses of IL-1β (priming) during glucose stimulated insulin secretion assays. *P < 0.05, **P < 0.001, ***P < 0.0001. Statistical significance (P) was determined by Student's t test and in (g-i) by ANOVA. All error bars denote s.e.m.

Supplementary Figure 4 Insulin stimulates the secretion of IL-1β by macrophages via metabolism and the NLRP3 inflammasome.

(a) InsR protein levels in naive (M0), pro-inflammatory M1 and alternative M2 polarized macrophages (n=3 experiments). (b) Insulin-induced (s473) phospho-AKT in M0, M1 and M2 polarized macrophages, data presented as ratio of insulin to non-insulin treated cells after normalization to total AKT (n=3 experiments). (c) Extracellular acidification rate (ECAR; mpH/min) from M0 or M2 polarized macrophages incubated for 2 hours in the presence or absence of 1 μg/ml insulin (n=12 and 15, respecively; 3 experiments). (d) Two-hour TNFα, IL-6, and CXCL1 secretion from 2 hour M1 polarized WT or Nlrp3-/- macrophages treated with or without 1 μg/ml insulin (n=5 mice each). (e) Gene expression profiles in M1 polarized macrophages with or without 2-hour treatment with 1 μg/ml insulin; data are expressed as fold change from untreated M0 controls (n=9, 3 experiments). (f) Cell survival as detected by annexin V and dapi staining of 2-hour M1 polarized macrophages treated for 2 hours with or without 1 μg/ml insulin. (g) Circulating CXCL1 protein concentration in mice treated with or without 1 unit/kg insulin (60 minutes post injection; n=10). *P < 0.05, **P<0.01. Statistical significance (P) was determined by ANOVA and in (g) by student’s t test. All error bars denote s.e.m.

Supplementary Figure 5 IL-1β shifts glucose uptake to immune cells.

(a) Blood glucose levels during an oral glucose tolerance (oGTT) 18 minutes after a single injection of 1 μg/kg IL-1β in Rag2-/- and littermate heterozygous mice (n=6-7). (b) Representative flow cytometry plot of peritoneal macrophage (CD11b+, F4/80+) depletion in Rag2-/- deficient mice 3 days after injection of liposomes containing clodronate or PBS.

Supplementary Figure 6 Proposed model for the physiological role of IL-1β and insulin in the regulation of glucose metabolism in response to food intake.

Food ingestion during feeding increases the number of peritoneal macrophages. These macrophages are stimulated by bacterial products and glucose to increase the production and release of IL-1β. Increased IL-1β concentrations will then enhance the continuous postprandial insulin secretion from pancreatic β cells via the highly expressed IL-1 receptor 1 (IL-1R1) and the IL-1 receptor-associated kinase-4 (IRAK4). The secreted insulin binds to its receptor (InsR) on macrophages, leading to enhanced glucose uptake through the glucose transporter GLUT1, AKT phosphorylation (pAKT) as well as hexokinase 2 (HK2) and glycolytic activity leading to ROS production. This further stimulates macrophage- derived pro-IL-1β-maturation by the NLRP3 inflammasome. Finally, increased levels of IL-1β and insulin stimulate glucose uptake into muscle, adipose tissue and immune cells that consequently decrease glycemia, thereby limiting the postprandial inflammatory response.

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Dror, E., Dalmas, E., Meier, D. et al. Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol 18, 283–292 (2017). https://doi.org/10.1038/ni.3659

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