Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden
Parasitic helminths, which infect an estimated two billion people worldwide, represent a significant global public health problem. Infection is associated with life-long morbidity including growth retardation and organ failure. Despite these debilitating conditions, there are currently no successful vaccines against helminths. Further, great variability in the host immune response to helminths exists, with the ability of some individuals to develop immunity, while others are susceptible when re-exposed or maintain life-long chronic infections. Identifying new factors that are differentially expressed in immune versus susceptible individuals could provide new targeting strategies for diagnosis or treatment of helminth infection. Here, we identify an important immunoregulatory function for human resistin in helminth infection. Employing transgenic mice in which the human resistin gene was inserted, we show that human resistin is induced by infection with the helminth Nippostrongylus brasiliensis, where it promotes excessive inflammation and impedes parasite killing. Moreover, analysis of clinical samples from two cohorts of individuals infected with filarial nematodes or soil-transmitted helminths revealed increased resistin and serum proinflammatory cytokines compared to putatively immune individuals. Together, these studies suggest that human resistin is a detrimental cytokine that is expressed in multiple helminth infections, mediates pathogenic inflammation, and delays parasite clearance.
Vyšlo v časopise:
Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004579
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004579
Souhrn
Parasitic helminths, which infect an estimated two billion people worldwide, represent a significant global public health problem. Infection is associated with life-long morbidity including growth retardation and organ failure. Despite these debilitating conditions, there are currently no successful vaccines against helminths. Further, great variability in the host immune response to helminths exists, with the ability of some individuals to develop immunity, while others are susceptible when re-exposed or maintain life-long chronic infections. Identifying new factors that are differentially expressed in immune versus susceptible individuals could provide new targeting strategies for diagnosis or treatment of helminth infection. Here, we identify an important immunoregulatory function for human resistin in helminth infection. Employing transgenic mice in which the human resistin gene was inserted, we show that human resistin is induced by infection with the helminth Nippostrongylus brasiliensis, where it promotes excessive inflammation and impedes parasite killing. Moreover, analysis of clinical samples from two cohorts of individuals infected with filarial nematodes or soil-transmitted helminths revealed increased resistin and serum proinflammatory cytokines compared to putatively immune individuals. Together, these studies suggest that human resistin is a detrimental cytokine that is expressed in multiple helminth infections, mediates pathogenic inflammation, and delays parasite clearance.
Zdroje
1. HotezPJ, BrindleyPJ, BethonyJM, KingCH, PearceEJ, et al. (2008) Helminth infections: the great neglected tropical diseases. J Clin Invest 118: 1311–1321.
2. MacDonaldTT, ChoyMY, SpencerJ, RichmanPI, DissT, et al. (1991) Histopathology and immunohistochemistry of the caecum in children with the Trichuris dysentery syndrome. J Clin Pathol 44: 194–199.
3. MinB, ProutM, Hu-LiJ, ZhuJ, JankovicD, et al. (2004) Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J Exp Med 200: 507–517.
4. NeillDR, WongSH, BellosiA, FlynnRJ, DalyM, et al. (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464: 1367–1370.
5. VoehringerD, ShinkaiK, LocksleyRM (2004) Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production. Immunity 20: 267–277.
6. Le GoffL, LambTJ, GrahamAL, HarcusY, AllenJE (2002) IL-4 is required to prevent filarial nematode development in resistant but not susceptible strains of mice. Int J Parasitol 32: 1277–1284.
7. UrbanJFJr, Noben-TrauthN, DonaldsonDD, MaddenKB, MorrisSC, et al. (1998) IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8: 255–264.
8. ChenF, LiuZ, WuW, RozoC, BowdridgeS, et al. (2012) An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med 18: 260–266.
9. HerbertDR, HolscherC, MohrsM, ArendseB, SchwegmannA, et al. (2004) Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20: 623–635.
10. UrbanJ, FangH, LiuQ, EkkensMJ, ChenSJ, et al. (2000) IL-13-mediated worm expulsion is B7 independent and IFN-gamma sensitive. J Immunol 164: 4250–4256.
11. BabuS, BhatSQ, Pavan KumarN, LipiraAB, KumarS, et al. (2009) Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells. PLoS Negl Trop Dis 3: e420.
12. BabuS, AnuradhaR, KumarNP, GeorgePJ, KumaraswamiV, et al. (2012) Toll-like receptor- and filarial antigen-mediated, mitogen-activated protein kinase- and NF-kappaB-dependent regulation of angiogenic growth factors in filarial lymphatic pathology. Infect Immun 80: 2509–2518.
13. HelmbyH, GrencisRK (2003) Essential role for TLR4 and MyD88 in the development of chronic intestinal nematode infection. Eur J Immunol 33: 2974–2979.
14. YangRZ, HuangQ, XuA, McLenithanJC, EisenJA, et al. (2003) Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun 310: 927–935.
15. NairMG, DuY, PerrigoueJG, ZaphC, TaylorJJ, et al. (2009) Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung. J Exp Med 206: 937–952.
16. PesceJT, RamalingamTR, WilsonMS, Mentink-KaneMM, ThompsonRW, et al. (2009) Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog 5: e1000393.
17. NairMG, GuildKJ, DuY, ZaphC, YancopoulosGD, et al. (2008) Goblet cell-derived resistin-like molecule beta augments CD4+ T cell production of IFN-gamma and infection-induced intestinal inflammation. J Immunol 181: 4709–4715.
18. ArtisD, WangML, KeilbaughSA, HeW, BrenesM, et al. (2004) RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci U S A 101: 13596–13600.
19. SteppanCM, BaileyST, BhatS, BrownEJ, BanerjeeRR, et al. (2001) The hormone resistin links obesity to diabetes. Nature 409: 307–312.
20. JungHS, ParkKH, ChoYM, ChungSS, ChoHJ, et al. (2006) Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc Res 69: 76–85.
21. PatelL, BuckelsAC, KinghornIJ, MurdockPR, HolbrookJD, et al. (2003) Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 300: 472–476.
22. MigitaK, MaedaY, MiyashitaT, KimuraH, NakamuraM, et al. (2006) The serum levels of resistin in rheumatoid arthritis patients. Clin Exp Rheumatol 24: 698–701.
23. ReillyMP, LehrkeM, WolfeML, RohatgiA, LazarMA, et al. (2005) Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 111: 932–939.
24. JiangS, ParkDW, TadieJM, GregoireM, DeshaneJ, et al. (2014) Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury. J Immunol 192: 4795–4803.
25. LehrkeM, ReillyMP, MillingtonSC, IqbalN, RaderDJ, et al. (2004) An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med 1: e45.
26. ParkHK, QatananiM, BriggsER, AhimaRS, LazarMA (2011) Inflammatory induction of human resistin causes insulin resistance in endotoxemic mice. Diabetes 60: 775–783.
27. KuoCH, ChenKF, ChouSH, HuangYF, WuCY, et al. (2013) Lung tumor-associated dendritic cell-derived resistin promoted cancer progression by increasing Wolf-Hirschhorn syndrome candidate 1/Twist pathway. Carcinogenesis 34: 2600–2609.
28. HsiehYY, ShenCH, HuangWS, ChinCC, KuoYH, et al. (2014) Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/NFkappaB signaling pathway in gastric cancer cells. J Biomed Sci 21: 59.
29. BenomarY, GertlerA, De LacyP, CrepinD, Ould HamoudaH, et al. (2013) Central resistin overexposure induces insulin resistance through Toll-like receptor 4. Diabetes 62: 102–114.
30. ReeceJJ, SiracusaMC, ScottAL (2006) Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages. Infect Immun 74: 4970–4981.
31. BoringL, GoslingJ, ChensueSW, KunkelSL, FareseRVJr, et al. (1997) Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J Clin Invest 100: 2552–2561.
32. TaubDD, LloydAR, ConlonK, WangJM, OrtaldoJR, et al. (1993) Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med 177: 1809–1814.
33. OdegaardJI, ChawlaA (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6: 275–297.
34. ThomasGD, RuckerlD, MaskreyBH, WhitfieldPD, BlaxterML, et al. (2012) The biology of nematode- and IL4Ralpha-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics. Blood 120: e93–e104.
35. LehrkeM, LazarMA (2004) Inflamed about obesity. Nat Med 10: 126–127.
36. JacksonJA, TurnerJD, KamalM, WrightV, BickleQ, et al. (2006) Gastrointestinal nematode infection is associated with variation in innate immune responsiveness. Microbes Infect 8: 487–492.
37. BethonyJ, BrookerS, AlbonicoM, GeigerSM, LoukasA, et al. (2006) Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 367: 1521–1532.
38. MoncayoAL, VacaM, OviedoG, WorkmanLJ, ChicoME, et al. (2013) Effects of geohelminth infection and age on the associations between allergen-specific IgE, skin test reactivity and wheeze: a case-control study. Clin Exp Allergy 43: 60–72.
39. LokeP, NairMG, ParkinsonJ, GuilianoD, BlaxterM, et al. (2002) IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol 3: 7.
40. NairMG, GallagherIJ, TaylorMD, LokeP, CoulsonPS, et al. (2005) Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun 73: 385–394.
41. CuencoKT, OttesenEA, WilliamsSA, NutmanTB, SteelC (2009) Heritable factors play a major role in determining host responses to Wuchereria bancrofti infection in an isolated South Pacific island population. J Infect Dis 200: 1271–1278.
42. WellerPF, OttesenEA, HeckL, TereT, NevaFA (1982) Endemic filariasis on a Pacific island. I. Clinical, epidemiologic, and parasitologic aspects. Am J Trop Med Hyg 31: 942–952.
43. AnthonyRM, RutitzkyLI, UrbanJFJr, StadeckerMJ, GauseWC (2007) Protective immune mechanisms in helminth infection. Nat Rev Immunol 7: 975–987.
44. HerbertDR, YangJQ, HoganSP, GroschwitzK, KhodounM, et al. (2009) Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med 206: 2947–2957.
45. HeW, WangML, JiangHQ, SteppanCM, ShinME, et al. (2003) Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology 125: 1388–1397.
46. OsborneLC, JoyceKL, AlenghatT, SonnenbergGF, GiacominPR, et al. (2013) Resistin-like molecule alpha promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation. J Immunol 190: 2292–2300.
47. QatananiM, SzwergoldNR, GreavesDR, AhimaRS, LazarMA (2009) Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest 119: 531–539.
48. BabuS, KumaraswamiV, NutmanTB (2009) Alternatively activated and immunoregulatory monocytes in human filarial infections. J Infect Dis 199: 1827–1837.
49. SemnaniRT, MahapatraL, MooreV, SanprasertV, NutmanTB (2011) Functional and phenotypic characteristics of alternative activation induced in human monocytes by interleukin-4 or the parasitic nematode Brugia malayi. Infect Immun 79: 3957–3965.
50. GanAM, ButoiED, ManeaA, SimionV, StanD, et al. (2013) Inflammatory effects of resistin on human smooth muscle cells: up-regulation of fractalkine and its receptor, CX3CR1 expression by TLR4 and Gi-protein pathways. Cell Tissue Res 351: 161–174.
51. SilswalN, SinghAK, ArunaB, MukhopadhyayS, GhoshS, et al. (2005) Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun 334: 1092–1101.
52. TarkowskiA, BjersingJ, ShestakovA, BokarewaMI (2010) Resistin competes with lipopolysaccharide for binding to toll-like receptor 4. J Cell Mol Med 14: 1419–1431.
53. PirvulescuMM, GanAM, StanD, SimionV, CalinM, et al. (2014) Subendothelial resistin enhances monocyte transmigration in a co-culture of human endothelial and smooth muscle cells by mechanisms involving fractalkine, MCP-1 and activation of TLR4 and Gi/o proteins signaling. Int J Biochem Cell Biol 50: 29–37.
54. LeeS, LeeHC, KwonYW, LeeSE, ChoY, et al. (2014) Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes. Cell Metab 19: 484–497.
55. AnuradhaR, GeorgePJ, Pavan KumarN, FayMP, KumaraswamiV, et al. (2012) Circulating microbial products and acute phase proteins as markers of pathogenesis in lymphatic filarial disease. PLoS Pathog 8: e1002749.
56. GeorgePJ, AnuradhaR, KumarNP, KumaraswamiV, NutmanTB, et al. (2012) Evidence of microbial translocation associated with perturbations in T cell and antigen-presenting cell homeostasis in hookworm infections. PLoS Negl Trop Dis 6: e1830.
57. BabuS, NutmanTB (2012) Immunopathogenesis of lymphatic filarial disease. Semin Immunopathol 34: 847–861.
58. WangJ, GustiV, SaraswatiA, LoDD (2011) Convergent and divergent development among M cell lineages in mouse mucosal epithelium. J Immunol 187: 5277–5285.
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2015 Číslo 1
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Infections in Humans and Animals: Pathophysiology, Detection, and Treatment
- The Phylogenetically-Related Pattern Recognition Receptors EFR and XA21 Recruit Similar Immune Signaling Components in Monocots and Dicots
- Specificity and Dynamics of Effector and Memory CD8 T Cell Responses in Human Tick-Borne Encephalitis Virus Infection
- Viral Activation of MK2-hsp27-p115RhoGEF-RhoA Signaling Axis Causes Cytoskeletal Rearrangements, P-body Disruption and ARE-mRNA Stabilization