Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver

English version České info

The ability of human pathogens, like HBV, HCV or Plasmodium spp. to infect the liver might be influenced by its tolerogenic features. However, hepatic tolerance is not absolute since protective immunity can be triggered. Our goal was to define how to deliberately elicit an intrahepatic protective immune response. To achieve this, we purified immune cells residing in the vascular bed of human livers and we probed their reactivity against different pathogen-associated molecules, mimicking signature components of viruses or bacteria. We found that robust production of anti-viral cytokine IFN-γ was induced only by the TLR8 agonist ssRNA40. Mechanistically, ssRNA40 triggered hepatic monocytes to produce IL-12 and IL-18 cytokines, which stimulated IFN-γ production by liver-resident CD161Bright MAIT and CD56Bright NK cells. We also demonstrated that ssRNA40-mediated activation could occur in pathologic (HBV -⁠ or HCV-chronically infected) livers and that a similar cytokine-mediated activation of intrahepatic cells could also be triggered upon bacterial infection. Thus, we showed that the liver immune cells can respond vigorously to specific pathogen-associated molecules. The selective production of IFN-γ by liver-resident cells could have therapeutic implications for the treatment of chronic liver infections.

Vyšlo v časopise: Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver. PLoS Pathog 10(6): e32767. doi:10.1371/journal.ppat.1004210
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004210

Souhrn

Zdroje

1. ProtzerU, MainiMK, KnollePA (2012) Living in the liver: hepatic infections. Nat Rev Immunol 12 : 201–213.

2. RazE (2007) Organ-specific regulation of innate immunity. Nat Immunol 8 : 3–4.

3. CrispeIN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27 : 147–163.

4. ChisariFV, NakamuraM, MilichDR, HanK, MoldenD, et al. (1985) Production of two distinct and independent hepatic immunoregulatory molecules by the perfused rat liver. Hepatology 5 : 735–743.

5. LeeWY, MoriartyTJ, WongCH, ZhouH, StrieterRM, et al. (2010) An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat Immunol 11 : 295–302.

6. TuZ, BozorgzadehA, PierceRH, KurtisJ, CrispeIN, et al. (2008) TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 205 : 233–244.

7. TreinerE, LantzO (2006) CD1d -⁠ and MR1-restricted invariant T cells: of mice and men. Curr Opin Immunol 18 : 519–526.

8. TangXZ, JoJ, TanAT, SandalovaE, ChiaA, et al. (2013) IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells. J Immunol 190 : 3142–3152.

9. BlasiusAL, BeutlerB (2010) Intracellular toll-like receptors. Immunity 32 : 305–315.

10. HeilF, HemmiH, HochreinH, AmpenbergerF, KirschningC, et al. (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303 : 1526–1529.

11. Kjer-NielsenL, PatelO, CorbettAJ, Le NoursJ, MeehanB, et al. (2012) MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491 : 717–723.

12. ChuaWJ, TruscottSM, EickhoffCS, BlazevicA, HoftDF, et al. (2012) Polyclonal mucosa-associated invariant T cells have unique innate functions in bacterial infection. Infect Immun 80 : 3256–3267.

13. UssherJE, BiltonM, AttwodE, ShadwellJ, RichardsonR, et al. (2014) CD161(++) CD8(+) T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur J Immunol 44 : 195–203.

14. CrosJ, CagnardN, WoollardK, PateyN, ZhangSY, et al. (2010) Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33 : 375–386.

15. CavanaughVJ, GuidottiLG, ChisariFV (1997) Interleukin-12 inhibits hepatitis B virus replication in transgenic mice. J Virol 71 : 3236–3243.

16. KimuraK, KakimiK, WielandS, GuidottiLG, ChisariFV (2002) Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. J Virol 76 : 10702–10707.

17. LauDT, NegashA, ChenJ, CrochetN, SinhaM, et al. (2013) Innate immune tolerance and the role of kupffer cells in differential responses to interferon therapy among patients with HCV genotype 1 infection. Gastroenterology 144 : 402–e412, 402-413, e412.

18. LanfordRE, GuerraB, ChavezD, GiavedoniL, HodaraVL, et al. (2013) GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees. Gastroenterology 144 : 1508–e1510, 1508-1517, e1510.

19. LiaskouE, ZimmermannHW, LiKK, OoYH, SureshS, et al. (2013) Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57 : 385–398.

20. PeppaD, MiccoL, JavaidA, KennedyPT, SchurichA, et al. (2010) Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog 6: e1001227.

21. CervantesJL, Dunham-EmsSM, La VakeCJ, PetzkeMM, SahayB, et al. (2011) Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-beta. Proc Natl Acad Sci U S A 108 : 3683–3688.

22. GantierMP, IrvingAT, Kaparakis-LiaskosM, XuD, EvansVA, et al. (2010) Genetic modulation of TLR8 response following bacterial phagocytosis. Hum Mutat 31 : 1069–1079.

23. KarikoK, BucksteinM, NiH, WeissmanD (2005) Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23 : 165–175.

24. SanderLE, DavisMJ, BoekschotenMV, AmsenD, DascherCC, et al. (2011) Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474 : 385–389.

25. Le BourhisL, MartinE, PeguilletI, GuihotA, FrouxN, et al. (2010) Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol 11 : 701–708.

26. HorsmansY, BergT, DesagerJP, MuellerT, SchottE, et al. (2005) Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology 42 : 724–731.

27. LeeJ, WuCC, LeeKJ, ChuangTH, KatakuraK, et al. (2006) Activation of anti-hepatitis C virus responses via Toll-like receptor 7. Proc Natl Acad Sci U S A 103 : 1828–1833.

28. DieboldSS, KaishoT, HemmiH, AkiraS, Reis e SousaC (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303 : 1529–1531.

29. GuidottiLG, RochfordR, ChungJ, ShapiroM, PurcellR, et al. (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science 284 : 825–829.

30. GuidottiLG, IshikawaT, HobbsMV, MatzkeB, SchreiberR, et al. (1996) Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4 : 25–36.

31. FosdickA, ZhengJ, PflanzS, FreyCR, HesselgesserJ, et al. (2014) Pharmacokinetic and Pharmacodynamic Properties of GS-9620, a Novel Toll-Like Receptor 7 Agonist, Demonstrate Interferon-Stimulated Gene Induction without Detectable Serum Interferon at Low Oral Doses. J Pharmacol Exp Ther 348 : 96–105.

32. SchurichA, PallettLJ, LubowieckiM, SinghHD, GillUS, et al. (2013) The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLoS Pathog 9: e1003208.

33. LanP, ZhangC, HanQ, ZhangJ, TianZ (2013) Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance. Hepatology 58 : 73–85.

34. TanAT, KohS, GohW, ZheHY, GehringAJ, et al. (2010) A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. J Hepatol 52 : 330–339.

35. SchenkelJM, FraserKA, VezysV, MasopustD (2013) Sensing and alarm function of resident memory CD8(+) T cells. Nat Immunol 14 : 509–513.

36. KakimiK, LaneTE, WielandS, AsensioVC, CampbellIL, et al. (2001) Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J Exp Med 194 : 1755–1766.

37. TumasDB, ZhengX, RhodesG, DuatschekP, HesselgesserJ, et al. (2011) Preclinical characterization of GS-9620, a potent and selective oral TLR7 agonist. J Hepatol 56: S180.