Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation

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Chitin is an essential structural polysaccharide of fungal pathogens and parasites, but its role in human immune responses remains largely unknown. It is the second most abundant polysaccharide in nature after cellulose and its derivatives today are widely used for medical and industrial purposes. We analysed the immunological properties of purified chitin particles derived from the opportunistic human fungal pathogen Candida albicans, which led to the selective secretion of the anti-inflammatory cytokine IL-10. We identified NOD2, TLR9 and the mannose receptor as essential fungal chitin-recognition receptors for the induction of this response. Chitin reduced LPS-induced inflammation in vivo and may therefore contribute to the resolution of the immune response once the pathogen has been defeated. Fungal chitin also induced eosinophilia in vivo, underpinning its ability to induce asthma. Polymorphisms in the identified chitin receptors, NOD2 and TLR9, predispose individuals to inflammatory conditions and dysregulated expression of chitinases and chitinase-like binding proteins, whose activity is essential to generate IL-10-inducing fungal chitin particles in vitro, have also been linked to inflammatory conditions and asthma. Chitin recognition is therefore critical for immune homeostasis and is likely to have a significant role in infectious and allergic disease.

Authors Summary:
Chitin is the second most abundant polysaccharide in nature after cellulose and an essential component of the cell wall of all fungal pathogens. The discovery of human chitinases and chitinase-like binding proteins indicates that fungal chitin is recognised by cells of the human immune system, shaping the immune response towards the invading pathogen. We show that three immune cell receptors –⁠ the mannose receptor, NOD2 and TLR9 recognise chitin and act together to mediate an anti-inflammatory response via secretion of the cytokine IL-10. This mechanism may prevent inflammation-based damage during fungal infection and restore immune balance after an infection has been cleared. By increasing the chitin content in the cell wall pathogenic fungi may influence the immune system in their favour, by down-regulating protective inflammatory immune responses. Furthermore, gene mutations and dysregulated enzyme activity in the described chitin recognition pathway are implicated in inflammatory conditions such as Crohn's Disease and asthma, highlighting the importance of the discovered mechanism in human health.

Vyšlo v časopise: Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004050
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004050

Souhrn

Zdroje

1. AraujoAC, Souto-PadronT, de SouzaW (1993) Cytochemical localization of carbohydrate residues in microfilariae of Wuchereria bancrofti and Brugia malayi. J Histochem Cytochem 41 : 571–578.

2. FuhrmanJA, PiessensWF (1985) Chitin synthesis and sheath morphogenesis in Brugia malayi microfilariae. Mol Biochem Parasitol 17 : 93–104.

3. NevilleAC, ParryDA, Woodhead-GallowayJ (1976) The chitin crystallite in arthropod cuticle. J Cell Sci 21 : 73–82.

4. ShahabuddinM, KaslowDC (1994) Plasmodium: parasite chitinase and its role in malaria transmission. Exp Parasitol 79 : 85–88.

5. BrownGD, DenningDW, GowNA, LevitzSM, NeteaMG, et al. (2012) Hidden killers: human fungal infections. Sci Transl Med 4 : 165rv113.

6. KlisFM, de GrootP, HellingwerfK (2001) Molecular organization of the cell wall of Candida albicans. Med Mycol 39 Suppl 1 : 1–8.

7. WalkerLA, MunroCA, de BruijnI, LenardonMD, McKinnonA, et al. (2008) Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog 4: e1000040.

8. LeeKK, MaccallumDM, JacobsenMD, WalkerLA, OddsFC, et al. (2011) Elevated cell wall chitin in Candida albicans confers echinocandin resistance in vivo. Antimicrob Agents Chemother 56 : 208–217.

9. SchlosserA, ThomsenT, MoellerJB, NielsenO, TornoeI, et al. (2009) Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183 : 3800–3809.

10. VegaK, KalkumM (2012) Chitin, chitinase responses, and invasive fungal infections. Int J Microbiol 2012 : 920459.

11. LeeCG, Da SilvaCA, Dela CruzCS, AhangariF, MaB, et al. (2010) Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol 73 : 479–501.

12. CashHL, WhithamCV, BehrendtCL, HooperLV (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313 : 1126–1130.

13. Da SilvaCA, ChalouniC, WilliamsA, HartlD, LeeCG, et al. (2009) Chitin is a size-dependent regulator of macrophage TNF and IL-10 production. J Immunol 182 : 3573–3582.

14. van EijkM, ScheijSS, van RoomenCP, SpeijerD, BootRG, et al. (2007) TLR -⁠ and NOD2-dependent regulation of human phagocyte-specific chitotriosidase. FEBS Lett 581 : 5389–5395.

15. Di RosaM, De GregorioC, MalaguarneraG, TuttobeneM, BiazzoF, et al. (2013) Evaluation of AMCase and CHIT-1 expression in monocyte macrophages lineage. Mol Cell Biochem 374 : 73–80.

16. van EijkM, Voorn-BrouwerT, ScheijSS, VerhoevenAJ, BootRG, et al. (2010) Curdlan-mediated regulation of human phagocyte-specific chitotriosidase. FEBS Lett 584 : 3165–3169.

17. van EijkM, van RoomenCP, RenkemaGH, BussinkAP, AndrewsL, et al. (2005) Characterization of human phagocyte-derived chitotriosidase, a component of innate immunity. Int Immunol 17 : 1505–1512.

18. MunroCA, SchofieldDA, GoodayGW, GowNA (1998) Regulation of chitin synthesis during dimorphic growth of Candida albicans. Microbiology 144(Pt 2): 391–401.

19. GoldmanDL, VicencioAG (2012) The chitin connection. MBio 3.

20. MuzzarelliRA (2010) Chitins and chitosans as immunoadjuvants and non-allergenic drug carriers. Mar Drugs 8 : 292–312.

21. MiyazatoA, NakamuraK, YamamotoN, Mora-MontesHM, TanakaM, et al. (2009) Toll-like receptor 9-dependent activation of myeloid dendritic cells by Deoxynucleic acids from Candida albicans. Infect Immun 77 : 3056–3064.

22. KasperkovitzPV, KhanNS, TamJM, MansourMK, DavidsPJ, et al. (2011) Toll-like receptor 9 modulates macrophage antifungal effector function during innate recognition of Candida albicans and Saccharomyces cerevisiae. Infect Immun 79 : 4858–4867.

23. van de VeerdonkFL, NeteaMG, JansenTJ, JacobsL, VerschuerenI, et al. (2008) Redundant role of TLR9 for anti-Candida host defense. Immunobiology 213 : 613–620.

24. RamaprakashH, HogaboamCM (2009) Intranasal CpG therapy attenuated experimental fungal asthma in a TLR9-dependent and -independent manner. Int Arch Allergy Immunol 152 : 98–112.

25. VissersJL, van EschBC, JeurinkPV, HofmanGA, van OosterhoutAJ (2004) Stimulation of allergen-loaded macrophages by TLR9-ligand potentiates IL-10-mediated suppression of allergic airway inflammation in mice. Respir Res 5 : 21.

26. MorettiS, BozzaS, D'AngeloC, CasagrandeA, Della FaziaMA, et al. (2012) Role of innate immune receptors in paradoxical caspofungin activity in vivo in preclinical aspergillosis. Antimicrob Agents Chemother 56 : 4268–4276.

27. LenardonMD, MunroCA, GowNA (2010) Chitin synthesis and fungal pathogenesis. Curr Opin Microbiol 13 : 416–423.

28. TorokHP, GlasJ, EndresI, TonenchiL, TeshomeMY, et al. (2009) Epistasis between Toll-like receptor-9 polymorphisms and variants in NOD2 and IL23R modulates susceptibility to Crohn's disease. Am J Gastroenterol 104 : 1723–1733.

29. HotteNS, SalimSY, TsoRH, AlbertEJ, BachP, et al. (2012) Patients with inflammatory bowel disease exhibit dysregulated responses to microbial DNA. PLoS One 7: e37932.

30. LecatA, PietteJ, Legrand-PoelsS (2010) The protein Nod2: an innate receptor more complex than previously assumed. Biochem Pharmacol 80 : 2021–2031.

31. MirandaLN, van der HeijdenIM, CostaSF, SousaAP, SienraRA, et al. (2009) Candida colonisation as a source for candidaemia. J Hosp Infect 72 : 9–16.

32. PoulainD, SendidB, Standaert-VitseA, FradinC, JouaultT, et al. (2009) Yeasts: neglected pathogens. Dig Dis 27 Suppl 1 : 104–110.

33. Standaert-VitseA, SendidB, JoossensM, FrancoisN, Vandewalle-El KhouryP, et al. (2009) Candida albicans colonization and ASCA in familial Crohn's disease. Am J Gastroenterol 104 : 1745–1753.

34. LiQ, WangC, TangC, HeQ, LiN, et al. (2013) Dysbiosis of Gut Fungal Microbiota is Associated With Mucosal Inflammation in Crohn's Disease. J Clin Gastroenterol [Epub ahead of print].

35. McDonaldDR (2012) TH17 deficiency in human disease. J Allergy Clin Immunol 129 : 1429–1435 quiz 1436–1427.

36. MaddurMS, MiossecP, KaveriSV, BayryJ (2012) Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 181 : 8–18.

37. WilkeCM, WangL, WeiS, KryczekI, HuangE, et al. (2011) Endogenous interleukin-10 constrains Th17 cells in patients with inflammatory bowel disease. J Transl Med 9 : 217.

38. HuberS, GaglianiN, EspluguesE, O'ConnorWJr, HuberFJ, et al. (2011) Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34 : 554–565.

39. NoguchiE, HommaY, KangX, NeteaMG, MaX (2009) A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nat Immunol 10 : 471–479.

40. JawharaS, HabibK, MaggiottoF, PignedeG, VandekerckoveP, et al. (2012) Modulation of intestinal inflammation by yeasts and cell wall extracts: strain dependence and unexpected anti-inflammatory role of glucan fractions. PLoS One 7: e40648.

41. NagataniK, WangS, LladoV, LauCW, LiZ, et al. (2012) Chitin microparticles for the control of intestinal inflammation. Inflamm Bowel Dis 18 : 1698–1710.

42. RomaniL, PuccettiP (2006) Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism. Trends Microbiol 14 : 183–189.

43. ReeseTA, LiangHE, TagerAM, LusterAD, Van RooijenN, et al. (2007) Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447 : 92–96.

44. Van DykenSJ, GarciaD, PorterP, HuangX, QuinlanPJ, et al. (2011) Fungal chitin from asthma-associated home environments induces eosinophilic lung infiltration. J Immunol 187 : 2261–2267.

45. BrandA, MacCallumDM, BrownAJ, GowNA, OddsFC (2004) Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus. Eukaryot Cell 3 : 900–909.

46. Mora-MontesHM, NeteaMG, FerwerdaG, LenardonMD, BrownGD, et al. (2011) Recognition and blocking of innate immunity cells by Candida albicans chitin. Infect Immun 79 : 1961–1970.

47. PlaineA, WalkerL, Da CostaG, Mora-MontesHM, McKinnonA, et al. (2008) Functional analysis of Candida albicans GPI-anchored proteins: roles in cell wall integrity and caspofungin sensitivity. Fungal Genet Biol 45 : 1404–1414.

48. MuzzarelliRA (1998) Colorimetric determination of chitosan. Anal Biochem 260 : 255–257.

49. KogisoM, NishiyamaA, ShinoharaT, NakamuraM, MizoguchiE, et al. (2011) Chitin particles induce size-dependent but carbohydrate-independent innate eosinophilia. J Leukoc Biol 90 : 167–176.

50. KannegantiTD, LamkanfiM, KimYG, ChenG, ParkJH, et al. (2007) Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26 : 433–443.

51. GorzelannyC, PoppelmannB, PappelbaumK, MoerschbacherBM, SchneiderSW (2010) Human macrophage activation triggered by chitotriosidase-mediated chitin and chitosan degradation. Biomaterials 31 : 8556–8563.

52. HallRA, BatesS, LenardonMD, MaccallumDM, WagenerJ, et al. (2013) The Mnn2 mannosyltransferase family modulates mannoprotein fibril length, immune recognition and virulence of Candida albicans. PLoS Pathog 9: e1003276.