Age‐associated elevation in TLR5 leads to increased inflammatory responses in the elderly

Abstract

Summary Aging is accompanied by a progressive decline in immune function. Studies have shown age‐related decreases in the expression and signaling efficiency of Toll‐like receptors (TLRs) in monocytes and dendritic cells and dysregulation of macrophage TLR3. Using a multivariable mixed effect model, we report a highly significant increase in TLR5‐induced production of IL‐8 from monocytes of older individuals ( P < 0.0001). Elevated IL‐8 is accompanied by increased expression of TLR5, both protein and mRNA, and by increased levels of TLR5‐mediated phosphorylation of MAPK p38 and ERK. We noted incomplete activation of NF‐κB in response to TLR5 signaling in monocytes of elderly donors, as reflected by the absence of an associated increase in the production of TNF‐α. Elevated TLR5 may provide a critical mechanism to enhance immune responsiveness in older individuals.

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References 40

1. 1.

   Akashi-Takamura S, Miyake K. TLR accessory molecules. Curr. Opin. Immunol. 2008;20:420-425.

   Not in our library10.1016/j.coi.2008.07.001

2. 2.

   Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT, Medzhitov R, Fikrig E, Flavell RA. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat. Med. 2002;8:878-884.

   Not in our library10.1038/nm732

3. 3.

   Bates JT, Honko AN, Graff AH, Kock ND, Mizel SB. Mucosal adjuvant activity of flagellin in aged mice. Mech. Ageing Dev. 2008;129:271-281.

   Not in our library10.1016/j.mad.2008.01.009

4. 4.

   Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, Kurnasov OV, Fort FL, Osterman AL, Didonato JA, Feinstein E, Gudkov AV. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008;320:226-230.

   Not in our library10.1126/science.1154986

5. 5.

   Conley ME. Immunodeficiency: UNC-93B gets a toll call. Trends Immunol. 2007;28:99-101.

   Not in our library10.1016/j.it.2007.01.001

6. 6.

   van Duin D, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, Medzhitov R, Shaw AC. Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J. Infect. Dis. 2007a;195:1590-1597.

   Not in our library10.1086/516788

7. 7.

   van Duin D, Thomas V, Mohanty S, Montgomery RR, Ginter S, Fikrig E, Allore HG, Medzhitov R, Shaw AC. Age-associated defect in human TLR1 function and expression. J. Immunol. 2007b;178:970-975.

   Not in our library10.4049/jimmunol.178.2.970

8. 8.

   Faham A, Altin JG. Antigen-containing liposomes engrafted with flagellin-related peptides are effective vaccines that can induce potent antitumor immunity and immunotherapeutic effect. J. Immunol. 2010;185:1744-1754.

   Not in our library10.4049/jimmunol.1000027

9. 9.

   Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J. Infect. Dis. 2009;200:172-180.

   Not in our library10.1086/599790

10. 10.

    Feuillet V, Medjane S, Mondor I, Demaria O, Pagni PP, Galan JE, Flavell RA, Alexopoulou L. Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Proc. Natl Acad. Sci. USA. 2006;103:12487-12492.

    Not in our library10.1073/pnas.0605200103

11. 11.

    Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 2007;128:92-105.

    Not in our library10.1016/j.mad.2006.11.016

12. 12.

    Hoffmann E, Dittrich-Breiholz O, Holtmann H, Kracht M. Multiple control of interleukin-8 gene expression. J. Leukoc. Biol. 2002;72:847-855.

    Not in our library

13. 13.

    Huleatt JW, Nakaar V, Desai P, Huang Y, Hewitt D, Jacobs A, Tang J, McDonald W, Song L, Evans RK, Umlauf S, Tussey L, Powell TJ. Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine. 2008;26:201-214.

    Not in our library10.1016/j.vaccine.2007.10.062

14. 14.

    Jacobs MD, Harrison SC. Structure of an IkappaBalpha/NF-kappaB complex. Cell. 1998;95:749-758.

    Not in our library10.1016/s0092-8674(00)81698-0

15. 15.

    Joo JH, Ryu JH, Kim CH, Kim HJ, Suh MS, Kim JO, Chung SY, Lee SN, Kim HM, Bae YS, Yoon JH. Dual oxidase 2 is essential for the toll-like receptor 5-mediated inflammatory response in airway mucosa. Antioxid. Redox Signal. 2011.

    Not in our library10.1089/ars.2011.3898

16. 16.

    Kawai T, Akira S. Antiviral signaling through pattern recognition receptors. J. Biochem. 2007;141:137-145.

    Not in our library10.1093/jb/mvm032

17. 17.

    Kinnebrew MA, Ubeda C, Zenewicz LA, Smith N, Flavell RA, Pamer EG. Bacterial flagellin stimulates toll-like receptor 5-dependent defense against vancomycin-resistant Enterococcus infection. J. Infect. Dis. 2010;201:534-543.

    Not in our library10.1086/650203

18. 18.

    Kong K-F, Delroux K, Wang X, Qian F, Arjona A, Malawista SE, Fikrig E, Montgomery RR. Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly. J. Virol. 2008;82:7613-7623.

    Not in our library10.1128/jvi.00618-08

19. 19.

    Leng J, Stout-Delgado HW, Kavita U, Jacobs A, Tang J, Du W, Tussey L, Goldstein DR. Efficacy of a vaccine that links viral epitopes to flagellin in protecting aged mice from influenza viral infection. Vaccine. 2011;29:8147-8155.

    Not in our library10.1016/j.vaccine.2011.08.027

20. 20.

    Leon B, Ardavin C. Monocyte-derived dendritic cells in innate and adaptive immunity. Immunol. Cell Biol. 2008;86:320-324.

    Not in our library10.1038/icb.2008.14

21. 21.

    Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat. Immunol. 2004;5:133-139.

    Not in our library10.1038/ni1033

22. 22.

    McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R, Keefer J, David J, Leng L, Bucala R. A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J. Exp. Med. 2006;203:1185-1196.

    Not in our library10.1084/jem.20052398

23. 23.

    McGlauchlen KS, Vogel LA. Ineffective humoral immunity in the elderly. Microbes Infect. 2003;5:1279-1284.

    Not in our library10.1016/j.micinf.2003.09.001

24. 24.

    Metz CN, Bucala R. Role of macrophage migration inhibitory factor in the regulation of the immune response. Adv. Immunol. 1997;66:197-223.

    Not in our library10.1016/s0065-2776(08)60598-2

25. 25.

    Mizel SB, Bates JT. Flagellin as an adjuvant: cellular mechanisms and potential. J. Immunol. 2010;185:5677-5682.

    Not in our library10.4049/jimmunol.1002156

26. 26.

    Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J. Immunol. 2010;184:2518-2527.

    Not in our library10.4049/jimmunol.0901022

27. 27.

    Pawelec G. Immunosenescence: impact in the young as well as the old? Mech. Ageing Dev. 1999;108:1-7.

    Not in our library10.1016/s0047-6374(99)00010-x

28. 28.

    Qian F, Wang X, Zhang l, Lin A, Zhao H, Fikrig E, Montgomery RR. Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J. Infect. Dis. 2011;203:1415-1424.

    Not in our library10.1093/infdis/jir048

29. 29.

    Rhee SH, Keates AC, Moyer MP, Pothoulakis C. MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells. J. Biol. Chem. 2004;279:25179-25188.

    Not in our library10.1074/jbc.m400967200

30. 30.

    Rosenstiel P, Derer S, Till A, Hasler R, Eberstein H, Bewig B, Nikolaus S, Nebel A, Schreiber S. Systematic expression profiling of innate immune genes defines a complex pattern of immunosenescence in peripheral and intestinal leukocytes. Genes Immun. 2008;9:103-114.

    Not in our library10.1038/sj.gene.6364454

31. 31.
    Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults · 2010

    No notice
32. 32.

    Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the innate immune system. Curr. Opin. Immunol. 2010;22:507-513.

    Not in our library10.1016/j.coi.2010.05.003

33. 33.

    Shaw AC, Panda A, Joshi S, Qian F, Allore H, Montgomery RR. Dysregulation of human toll-like receptor function in aging. Ageing Res. Rev. 2011;10:346-353.

    Not in our library10.1016/j.arr.2010.10.007

34. 34.

    Skountzou I, Martin MD, Wang B, Ye L, Koutsonanos D, Weldon W, Jacob J, Compans RW. Salmonella flagellins are potent adjuvants for intranasally administered whole inactivated influenza vaccine. Vaccine. 2009;28:4103-4112.

    Not in our library10.1016/j.vaccine.2009.07.058

35. 35.

    Song L, Zhang Y, Yun NE, Poussard AL, Smith JN, Smith JK, Borisevich V, Linde JJ, Zacks MA, Li H, Kavita U, Reiserova L, Liu X, Dumuren K, Balasubramanian B, Weaver B, Parent J, Umlauf S, Liu G, Huleatt J, Tussey L, Paessler S. Superior efficacy of a recombinant flagellin: H5N1 HA globular head vaccine is determined by the placement of the globular head within flagellin. Vaccine. 2009;27:5875-5884.

    Not in our library10.1016/j.vaccine.2009.07.060

36. 36.

    Takahashi K, Shibata T, Akashi-Takamura S, Kiyokawa T, Wakabayashi Y, Tanimura N, Kobayashi T, Matsumoto F, Fukui R, Kouro T, Nagai Y, Takatsu K, Saitoh S, Miyake K. A protein associated with toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. J. Exp. Med. 2007;204:2963-2976.

    Not in our library10.1084/jem.20071132

37. 37.

    Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol. 2005;17:1-14.

    Not in our library10.1093/intimm/dxh186

38. 38.

    Taylor DN, Treanor JJ, Strout C, Johnson C, Fitzgerald T, Kavita U, Ozer K, Tussey L, Shaw A. Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI). Vaccine. 2011;29:4897-4902.

    Not in our library10.1016/j.vaccine.2011.05.001

39. 39.

    Yu Y, Zeng H, Lyons S, Carlson A, Merlin D, Neish AS, Gewirtz AT. TLR5-mediated activation of p38 MAPK regulates epithelial IL-8 expression via posttranscriptional mechanism. Am. J. Physiol. 2003;285:G282-G290.

    Not in our library10.1152/ajpgi.00503.2002

40. 40.

    Zeng H, Wu H, Sloane V, Jones R, Yu Y, Lin P, Gewirtz AT, Neish AS. Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. Am. J. Physiol. 2006;290:G96-G108.

    Not in our library10.1152/ajpgi.00273.2005

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