Cell Type-Specific Immunomodulation Induced by Helminthes: Effect on Metainflammation, Insulin Resistance and Type-2 Diabetes

Vivekanandhan Aravindhan Department of Genetics, Dr ALM PG IBMS, University of Madras, Chennai, India;

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Gowrishankar Anand AU-KBC Research Centre, MIT Campus of Anna University, Chennai, India

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Recent epidemiological studies have documented an inverse relationship between the decreasing prevalence of helminth infections and the increasing prevalence of metabolic diseases (“metabolic hygiene hypothesis”). Chronic inflammation leading to insulin resistance (IR) has now been identified as a major etiological factor for a variety of metabolic diseases other than obesity and Type-2 diabetes (metainflammation). One way by which helminth infections such as filariasis can modulate IR is by inducing a chronic, nonspecific, low-grade, immune suppression mediated by modified T-helper 2 (Th2) response (induction of both Th2 and regulatory T cells) which can in turn suppress the proinflammatory responses and promote insulin sensitivity (IS). This article provides evidence on how the cross talk between the innate and adaptive arms of the immune responses can modulate IR/sensitivity. The cross talk between innate (macrophages, dendritic cells, natural killer cells, natural killer T cells, myeloid derived suppressor cells, innate lymphoid cells, basophils, eosinophils, and neutrophils) and adaptive (helper T [CD4+] cells, cytotoxic T [CD8+] cells and B cells) immune cells forms two opposing circuits, one associated with IR and the other associated with IS under the conditions of metabolic syndrome and helminth-mediated immunomodulation, respectively.

Author Notes

Address correspondence to Vivekanandhan Aravindhan, Department of Genetics, Dr ALM PG IBMS, University of Madras, Taramani, Chennai, Tamil Nadu 600113, India. E-mail: cvaravindhan@gmail.com

These authors contributed equally to this work.

Financial support: The Department of Genetics, University of Madras, has received funds for infrastructural support from DST-FIST and UGC-SAP programs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ addresses: Vivekanandhan Aravindhan, Department of Genetics, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India, E-mail: cvaravindhan@gmail.com. Gowrishankar Anand, Department of Molecular Immunology, Anna University-K B Chandrasekhar Research Centre, Chennai, Tamil Nadu, India, E-mail: anandgshankar@gmail.co.

  • 1.

    Astrup A, Finer N, 2000. Redefining type 2 diabetes: ‘diabesity’ or ‘obesity dependent diabetes mellitus’? Obes Rev 1: 5759.

  • 2.

    Hotamisligil GS, 2006. Inflammation and metabolic disorders. Nature 444: 860867.

  • 3.

    Lumeng CN, Saltiel AR, 2011. Inflammatory links between obesity and metabolic disease. J Clin Invest 121: 21112117.

  • 4.

    Aravindhan V, Madhumitha H, 2016. Metainflammation in diabetic coronary artery disease: emerging role of innate and adaptive immune responses. J Diabetes Res 2016: 6264149.

    • Search Google Scholar
    • Export Citation
  • 5.

    Ding H, Triggle CR, 2005. Endothelial cell dysfunction and the vascular complications associated with type 2 diabetes: assessing the health of the endothelium. Vasc Health Risk Manag 1: 5571.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kendall DM, Harmel AP, 2002. The metabolic syndrome, type 2 diabetes, and cardiovascular disease: understanding the role of insulin resistance. Am J Manag Care 8: S635S653; quiz S654–S657.

    • Search Google Scholar
    • Export Citation
  • 7.

    Pedersen O, 1999. Genetics of insulin resistance. Exp Clin Endocrinol Diabetes 107: 113118.

  • 8.

    Reaven GM, 1988. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37: 15951607.

  • 9.

    Hong Y, Pedersen NL, Brismar K, de Faire U, 1997. Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am J Hum Genet 60: 143152.

    • Search Google Scholar
    • Export Citation
  • 10.

    Bell DS, 2000. Inflammation, insulin resistance, infection, diabetes, and atherosclerosis. Endocr Pract 6: 272276.

  • 11.

    Liu Q, Sundar K, Mishra PK, Mousavi G, Liu Z, Gaydo A, Alem F, Lagunoff D, Bleich D, Gause WC, 2009. Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms. Infect Immun 77: 53475358.

    • Search Google Scholar
    • Export Citation
  • 12.

    Hübner MP et al. 2012. Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β. J Immunol 188: 559568.

    • Search Google Scholar
    • Export Citation
  • 13.

    Hübner MP, Stocker JT, Mitre E, 2009. Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology 127: 512522.

    • Search Google Scholar
    • Export Citation
  • 14.

    Hussaarts L et al. 2015. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J 29: 30273039.

    • Search Google Scholar
    • Export Citation
  • 15.

    Berbudi A et al. 2016. Filarial infection or antigen administration improves glucose tolerance in diet-induced obese mice. J Innate Immun 8: 601616.

    • Search Google Scholar
    • Export Citation
  • 16.

    Yang Z et al. 2013. Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity. Infect Immun 81: 19051914.

    • Search Google Scholar
    • Export Citation
  • 17.

    Aravindhan V, Mohan V, Surendar J, Rao MM, Ranjani H, Kumaraswami V, Nutman TB, Babu S, 2010. Decreased prevalence of lymphatic filariasis among subjects with type-1 diabetes. Am J Trop Med Hyg 83: 13361339.

    • Search Google Scholar
    • Export Citation
  • 18.

    Aravindhan V, Mohan V, Surendar J, Muralidhara Rao M, Pavankumar N, Deepa M, Rajagopalan R, Kumaraswami V, Nutman TB, Babu S, 2010. Decreased prevalence of lymphatic filariasis among diabetic subjects associated with a diminished pro-inflammatory cytokine response (CURES 83). PLoS Negl Trop Dis 4: e707.

    • Search Google Scholar
    • Export Citation
  • 19.

    Aravindhan V, Mohan V, Surendar J, Rao MM, Anuradha R, Deepa M, Babu S, 2012. Effect of filarial infection on serum inflammatory and atherogenic biomarkers in coronary artery disease (CURES-121). Am J Trop Med Hyg 86: 828833.

    • Search Google Scholar
    • Export Citation
  • 20.

    Wiria AE et al. 2015. Infection with soil-transmitted helminths is associated with increased insulin sensitivity. PLoS One 10: e0127746.

  • 21.

    Hewitson JP, Grainger JR, Maizels RM, 2009. Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol Biochem Parasitol 167: 111.

    • Search Google Scholar
    • Export Citation
  • 22.

    Venugopal PG, Nutman TB, Semnani RT, 2009. Activation and regulation of toll-like receptors (TLRs) by helminth parasites. Immunol Res 43: 252263. Erratum in: PLoS One 2015;10(8).

    • Search Google Scholar
    • Export Citation
  • 23.

    Tahapary DL et al. 2017. Effect of anthelmintic treatment on insulin resistance: a cluster-randomized placebo-controlled trial in Indonesia. Clin Infect Dis 65: 764771.

    • Search Google Scholar
    • Export Citation
  • 24.

    Crowe J, Lumb FE, Harnett MM, Harnett W, 2017. Parasite excretory-secretory products and their effects on metabolic syndrome. Parasite Immunol 39(5).

    • Search Google Scholar
    • Export Citation
  • 25.

    Shanker A, Thounaojam MC, Mishra MK, Dikov MM, Uzhachenko RV, 2015. Innate-adaptive immune crosstalk. J Immunol Res 2015: 982465.

  • 26.

    Cheroutre H, Huang Y, 2013. Crosstalk between adaptive and innate immune cells leads to high quality immune protection at the mucosal borders. Adv Exp Med Biol 785: 4347.

    • Search Google Scholar
    • Export Citation
  • 27.

    Kambayashi T, Laufer TM, 2014. Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nat Rev Immunol 14: 719730.

    • Search Google Scholar
    • Export Citation
  • 28.

    Tsuji T, 1976. Subcutaneous fat necrosis of the newborn: light and electron microscopic studies. Br J Dermatol 95: 407416.

  • 29.

    Xu H et al. 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112: 18211830.

    • Search Google Scholar
    • Export Citation
  • 30.

    Murray PJ et al. 2014. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41: 1420.

  • 31.

    Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, Shen Y, Czech MP, Aouadi M, 2014. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab 19: 162171.

    • Search Google Scholar
    • Export Citation
  • 32.

    Fujisaka S et al. 2009. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58: 25742582.

  • 33.

    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr, 2003. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 17961808.

    • Search Google Scholar
    • Export Citation
  • 34.

    Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR, 2008. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57: 32393246.

    • Search Google Scholar
    • Export Citation
  • 35.

    Sun K, Kusminski CM, Scherer PE, 2011. Adipose tissue remodeling and obesity. J Clin Invest 121: 20942101.

  • 36.

    Suganami T, Ogawa Y, 2010. Adipose tissue macrophages: their role in adipose tissue remodeling. J Leukoc Biol 88: 3339.

  • 37.

    Heilbronn LK, Campbell LV, 2008. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 14: 12251230.

    • Search Google Scholar
    • Export Citation
  • 38.

    Lumeng CN, Bodzin JL, Saltiel AR, 2007. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175184.

    • Search Google Scholar
    • Export Citation
  • 39.

    Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW Jr, 2006. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116: 115124.

    • Search Google Scholar
    • Export Citation
  • 40.

    Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG, 2008. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8: 301309.

    • Search Google Scholar
    • Export Citation
  • 41.

    Herbert DR et al. 2004. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20: 623635.

    • Search Google Scholar
    • Export Citation
  • 42.

    Nair MG, Cochrane DW, Allen JE, 2003. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett 85: 173180.

    • Search Google Scholar
    • Export Citation
  • 43.

    Noel W, Raes G, Hassanzadeh Ghassabeh G, De Baetselier P, Beschin A, 2004. Alternatively activated macrophages during parasite infections. Trends Parasitol 20: 126133.

    • Search Google Scholar
    • Export Citation
  • 44.

    Loke P, Gallagher I, Nair MG, Zang X, Brombacher F, Mohrs M, Allison JP, Allen JE, 2007. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J Immunol 179: 39263936.

    • Search Google Scholar
    • Export Citation
  • 45.

    Reyes JL, Terrazas LI, 2007. The divergent roles of alternatively activated macrophages in helminthic infections. Parasite Immunol 29: 609619.

    • Search Google Scholar
    • Export Citation
  • 46.

    Maizels RM, Yazdanbakhsh M, 2003. Immune regulation by helminth parasites: cellular and molecular mechanisms. Nat Rev Immunol 3: 733744.

  • 47.

    Stefanovic-Racic M et al. 2012. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 61: 23302339.

    • Search Google Scholar
    • Export Citation
  • 48.

    Stefanovic-Racic M et al. 2012. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 61: 23302339.

    • Search Google Scholar
    • Export Citation
  • 49.

    Bertola A et al. 2012. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61: 22382247.

    • Search Google Scholar
    • Export Citation
  • 50.

    Terrazas CA, Terrazas LI, Gomez-Garcia L, 2010. Modulation of dendritic cell responses by parasites: a common strategy to survive. J Biomed Biotechnol 2010: 357106.

    • Search Google Scholar
    • Export Citation
  • 51.

    Kane CM, Jung E, Pearce EJ, 2008. Schistosoma mansoni egg antigen-mediated modulation of Toll-like receptor (TLR)-induced activation occurs independently of TLR2, TLR4, and MyD88. Infect Immun 76: 57545759.

    • Search Google Scholar
    • Export Citation
  • 52.

    Goodridge HS, Marshall FA, Else KJ, Houston KM, Egan C, Al-Riyami L, Liew FY, Harnett W, Harnett MM, 2005. Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62. J Immunol 174: 284293.

    • Search Google Scholar
    • Export Citation
  • 53.

    Terrazas CA, Terrazas LI, Gomez-Garcia L, 2010. Modulation of dendritic cell responses by parasites: a common strategy to survive. J Biomed Biotechnol 2010: 357106.

    • Search Google Scholar
    • Export Citation
  • 54.

    Vannella KM et al. 2016. Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci Transl Med 8: 337ra65.

    • Search Google Scholar
    • Export Citation
  • 55.

    Anand G, Vasanthakumar R, Mohan V, Babu S, Aravindhan V, 2015. Increased IL-12 and decreased IL-33 serum levels are associated with increased Th1 and suppressed Th2 cytokine profile in patients with diabetic nephropathy (CURES-134). Int J Clin Exp Pathol 7: 80088015.

    • Search Google Scholar
    • Export Citation
  • 56.

    Nutman TB, 2015. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths. Parasite Immunol 37: 304313.

  • 57.

    Semnani RT, Liu AY, Sabzevari H, Kubofcik J, Zhou J, Gilden JK, Nutman TB, 2003. Brugia malayi microfilariae induce cell death in human dendritic cells, inhibit their ability to make IL-12 and IL-10, and reduce their capacity to activate CD4+ T cells. J Immunol 171: 19501960.