Absence of Intestinal PPARγ Aggravates Acute Infectious Colitis in Mice through a Lipocalin-2–Dependent Pathway

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To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ) expression in intestinal epithelial cells. Interestingly, this PPARγ down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2). Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPARγ and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion.

Vyšlo v časopise: Absence of Intestinal PPARγ Aggravates Acute Infectious Colitis in Mice through a Lipocalin-2–Dependent Pathway. PLoS Pathog 10(1): e32767. doi:10.1371/journal.ppat.1003887
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003887

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1. BaumlerAJ, TsolisRM, FichtTA, AdamsLG (1998) Evolution of host adaptation in Salmonella enterica. Infection and Immunity 66: 4579–4587.

2. BarthelM, HapfelmeierS, Quintanilla-MartinezL, KremerM, RohdeM, et al. (2003) Pretreatment of Mice with Streptomycin Provides a Salmonella enterica Serovar Typhimurium Colitis Model That Allows Analysis of Both Pathogen and Host. Infection and Immunity 71: 2839–2858.

3. GeddesK, RubinoSJ, MagalhaesJG, StreutkerC, Le BourhisL, et al. (2011) Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nature medicine 17: 837–844.

4. RaffatelluM, GeorgeMD, AkiyamaY, HornsbyMJ, NuccioSP, et al. (2009) Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell host & microbe 5: 476–486.

5. BettelliE, KornT, OukkaM, KuchrooVK (2008) Induction and effector functions of T(H)17 cells. Nature 453: 1051–1057.

6. ColonnaM (2009) Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31: 15–23.

7. OuyangW, KollsJK, ZhengY (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28: 454–467.

8. KjeldsenL, JohnsenAH, SengelovH, BorregaardN (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. The Journal of biological chemistry 268: 10425–10432.

9. TriebelS, BlaserJ, ReinkeH, TschescheH (1992) A 25 kDa alpha 2-microglobulin-related protein is a component of the 125 kDa form of human gelatinase. FEBS letters 314: 386–388.

10. YanL, BorregaardN, KjeldsenL, MosesMA (2001) The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. The Journal of biological chemistry 276: 37258–37265.

11. BergerT, TogawaA, DuncanGS, EliaAJ, You-TenA, et al. (2006) Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proceedings of the National Academy of Sciences of the United States of America 103: 1834–1839.

12. FloTH, SmithKD, SatoS, RodriguezDJ, HolmesMA, et al. (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432: 917–921.

13. RaffatelluM, BaumlerAJ (2010) Salmonella's iron armor for battling the host and its microbiota. Gut microbes 1: 70–72.

14. StecherB, RobbianiR, WalkerAW, WestendorfAM, BarthelM, et al. (2007) Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS biology 5: 2177–2189.

15. FischbachMA, LinH, ZhouL, YuY, AbergelRJ, et al. (2006) The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proceedings of the National Academy of Sciences of the United States of America 103: 16502–16507.

16. HantkeK, NicholsonG, RabschW, WinkelmannG (2003) Salmochelins, siderophores of Salmonella enterica and uropathogenic Escherichia coli strains, are recognized by the outer membrane receptor IroN. Proceedings of the National Academy of Sciences of the United States of America 100: 3677–3682.

17. KonturekPC, KaniaJ, KukharskyV, RaithelM, OckerM, et al. (2004) Implication of peroxisome proliferator-activated receptor gamma and proinflammatory cytokines in gastric carcinogenesis: link to Helicobacter pylori-infection. Journal of pharmacological sciences 96: 134–143.

18. MahajanS, DkharHK, ChandraV, DaveS, NanduriR, et al. (2012) Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARgamma and TR4 for survival. Journal of immunology 188: 5593–5603.

19. KunduP, DeR, PalI, MukhopadhyayAK, SahaDR, et al. (2011) Curcumin alleviates matrix metalloproteinase-3 and -9 activities during eradication of Helicobacter pylori infection in cultured cells and mice. PloS one 6: e16306.

20. AdachiM, KurotaniR, MorimuraK, ShahY, SanfordM, et al. (2006) Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut 55: 1104–1113.

21. DreyerC, KreyG, KellerH, GivelF, HelftenbeinG, et al. (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68: 879–887.

22. MansenA, Guardiola-DiazH, RafterJ, BrantingC, GustafssonJA (1996) Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochemical and biophysical research communications 222: 844–851.

23. RicoteM, LiAC, WillsonTM, KellyCJ, GlassCK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391: 79–82.

24. WahliW, MichalikL (2012) PPARs at the crossroads of lipid signaling and inflammation. Trends in endocrinology and metabolism: TEM 23: 351–363.

25. SuCG, WenX, BaileyST, JiangW, RangwalaSM, et al. (1999) A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. The Journal of clinical investigation 104: 383–389.

26. YangXY, WangLH, ChenT, HodgeDR, ResauJH, et al. (2000) Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. The Journal of biological chemistry 275: 4541–4544.

27. Bassaganya-RieraJ, ReynoldsK, Martino-CattS, CuiY, HennighausenL, et al. (2004) Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease. Gastroenterology 127: 777–791.

28. DesreumauxP, DubuquoyL, NuttenS, PeuchmaurM, EnglaroW, et al. (2001) Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. The Journal of experimental medicine 193: 827–838.

29. DubuquoyL, DharancyS, NuttenS, PetterssonS, AuwerxJ, et al. (2002) Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet 360: 1410–1418.

30. KatayamaK, WadaK, NakajimaA, MizuguchiH, HayakawaT, et al. (2003) A novel PPAR gamma gene therapy to control inflammation associated with inflammatory bowel disease in a murine model. Gastroenterology 124: 1315–1324.

31. LytleC, TodTJ, VoKT, LeeJW, AtkinsonRD, et al. (2005) The peroxisome proliferator-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency. Inflammatory bowel diseases 11: 231–243.

32. NakajimaA, WadaK, MikiH, KubotaN, NakajimaN, et al. (2001) Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury. Gastroenterology 120: 460–469.

33. SaubermannLJ, NakajimaA, WadaK, ZhaoS, TerauchiY, et al. (2002) Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis. Inflammatory bowel diseases 8: 330–339.

34. NecelaBM, SuW, ThompsonEA (2008) Toll-like receptor 4 mediates cross-talk between peroxisome proliferator-activated receptor gamma and nuclear factor-kappaB in macrophages. Immunology 125: 344–358.

35. AreA, AronssonL, WangS, GreiciusG, LeeYK, et al. (2008) Enterococcus faecalis from newborn babies regulate endogenous PPARgamma activity and IL-10 levels in colonic epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 105: 1943–1948.

36. KellyD, CampbellJI, KingTP, GrantG, JanssonEA, et al. (2004) Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nature immunology 5: 104–112.

37. ZhengY, ValdezPA, DanilenkoDM, HuY, SaSM, et al. (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature medicine 14: 282–289.

38. BergerT, CheungCC, EliaAJ, MakTW (2010) Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proceedings of the National Academy of Sciences of the United States of America 107: 2995–3000.

39. LengX, DingT, LinH, WangY, HuL, et al. (2009) Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. Cancer research 69: 8579–8584.

40. DubuquoyL, JanssonEA, DeebS, RakotobeS, KarouiM, et al. (2003) Impaired expression of peroxisome proliferator-activated receptor gamma in ulcerative colitis. Gastroenterology 124: 1265–1276.

41. FlorinL, HummerichL, DittrichBT, KokocinskiF, WrobelG, et al. (2004) Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing. Oncogene 23: 7005–7017.

42. LiC, ChanYR (2011) Lipocalin 2 regulation and its complex role in inflammation and cancer. Cytokine 56: 435–441.

43. KunduP, MukhopadhyayAK, PatraR, BanerjeeA, BergDE, et al. (2006) Cag pathogenicity island-independent up-regulation of matrix metalloproteinases-9 and -2 secretion and expression in mice by Helicobacter pylori infection. The Journal of biological chemistry 281: 34651–34662.

44. CastanedaFE, WaliaB, Vijay-KumarM, PatelNR, RoserS, et al. (2005) Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: central role of epithelial-derived MMP. Gastroenterology 129: 1991–2008.

45. GargP, Vijay-KumarM, WangL, GewirtzAT, MerlinD, et al. (2009) Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. American journal of physiology Gastrointestinal and liver physiology 296: G175–184.

46. BrinckerhoffCE, MatrisianLM (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nature reviews Molecular cell biology 3: 207–214.

47. HoisethSK, StockerBA (1981) Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291: 238–239.

48. ImaiT, TakakuwaR, MarchandS, DentzE, BornertJM, et al. (2004) Peroxisome proliferator-activated receptor gamma is required in mature white and brown adipocytes for their survival in the mouse. Proceedings of the National Academy of Sciences of the United States of America 101: 4543–4547.

49. WlodarskaM, WillingB, KeeneyKM, MenendezA, BergstromKS, et al. (2011) Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis. Infection and Immunity 79: 1536–1545.

50. SchreiberE, MatthiasP, MullerMM, SchaffnerW (1989) Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic acids research 17: 6419.