Osteoprotegerin mediate RANK/RANKL signaling inhibition eases asthma inflammatory reaction by affecting the survival and function of dendritic cells

Main Article Content

X. Yang
X. Wang
M. Chi
M. Zhang
H. Shan
Q.-H. Zhang
J. Zhang
J. Shi
J.-Z. Zhang
R.-M. Wu
Y.-L. Li

Keywords

Asthma, Osteoprotegerin, RANK/RANKL, Dendritic cells

Abstract

Introduction: Asthma is a chronic inflammatory, heterogeneous airway disease affecting millions of people around the world. Dendritic cells (DCs) are considered the most important antigen-presenting cell in asthma airway inflammatory reaction. But whether osteoprotegerin (OPG) mediate RANK/RANKL signaling inhibition influences asthma development by affecting the survival and function of DCs remains unclear. In this study, we assessed the effects of OPG on DCs and asthma.


Material and methods: BALB/c mice immunized with ovalbumin (OVA) were challenged thrice with an aerosol of OVA every second day for eight days. Dexamethasone (1.0 mg/kg) or OPG (50g/kg) was administered intraperitoneally to OVA-immunized BALB/c mice on day 24 once a day for nine days. Mice were analyzed for effects of OPG on asthma, inflammatory cell infiltration and cytokine levels in lung tissue. The expression of RANK and -actin was detected by Western Blot. DCs were isolated from mouse bone morrow. Cell survival was assessed by cell counting. The content of IL-12 was detected by ELISA.


Results: Results showed that OVA increased the number of inflammatory factors in BALF, elevated lung inflammation scores in mice. OPG reversed the alterations induced by OVA in the asthmatic mice. OPG inhibited the survival and function of DC via inhibition of RANK/RANKL signaling.


Conclusions: This research proved inhibition of RANK/RANKL signaling by OPG could ease the inflammatory reaction in asthma, providing new evidence for the application of OPG on asthma.

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References

1. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31:143-78.

2. Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, et al. A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J. 2015;46:622-39.

3. Maarsingh H, Dekkers BG, Zuidhof AB, Bos IS, Menzen MH, Klein T, et al. Increased arginase activity contributes to airway remodelling in chronic allergic asthma. Eur Respir J. 2011;38:318-28.

4. Mackenzie B, Andrade-Sousa AS, Oliveira-Junior MC, Assumpcao-Neto E, Brandao-Rangel MA, Silva-Renno A, et al. Dendritic cells are involved in the effects of exercise in a model of asthma. Med Sci Sports Exerc. 2016;48:1459-67.

5. Lambrecht BN, Hammad H. Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu Rev Immunol. 2012;30:243-70.

6. Plantinga M, Guilliams M, Vanheerswynghels M, Deswarte K, Branco-Madeira F, Toussaint W, et al. Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity. 2013;38:322-35.

7. Schmudde I, Laumonnier Y, Kohl J. Anaphylatoxins coordinate innate and adaptive immune responses in allergic asthma. Semin Immunol. 2013;25:2-11.

8. Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One. 2012;7:e44552.

9. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165-76.

10. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998;95:3597-602.

11. Lee JW, Kobayashi Y, Nakamichi Y, Udagawa N, Takahashi N, Im NK, et al. Alisol-B, a novel phyto-steroid, suppresses the RANKLinduced osteoclast formation and prevents bone loss in mice. Biochem Pharmacol. 2010;80:352-61.

12. Teng YT. The role of acquired immunity and periodontal disease progression. Crit Rev Oral Biol Med. 2003;14:237-52.

13. Houri-Haddad Y, Wilensky A, Shapira L. T-cell phenotype as a risk factor for periodontal disease. Periodontol. 2007;45:67-75.

14. Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 1997;186:2075-80.

15. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390:175-9.

16. Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J Biol Chem. 1998;273:28355-9.

17. Josien R, Wong BR, Li HL, Steinman RM, Choi Y. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J Immunol. 1999;162:2562-8.

18. Williamson E, Bilsborough JM, Viney JL. Regulation of mucosal dendritic cell function by receptor activator of NF-kappa B (RANK)/RANK ligand interactions: impact on tolerance induction. J Immunol. 2002;169:3606-12.

19. Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA. Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity. 2002;16:257-70.

20. Wong BR, Besser D, Kim N, Arron JR, Vologodskaia M, Hanafusa H, et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell. 1999;4:1041-9.

21. Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996;183:195-201.

22. Qu SY, Ou-Yang HF, He YL, Wan Q, Shi JR, Wu CG. Der p 2 recombinant Bacille Calmette-Guerin targets dendritic cells to inhibit allergic airway inflammation in a mouse model of asthma. Respiration. 2013;85:49-58.

23. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001;344:350-62.

24. Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, et al. A new perspective on concepts of asthma severity and control. Eur Respir J. 2008;32:545-54.

25. Tschernig T, Neumann D, Pich A, Dorsch M, Pabst R. Experimental bronchial asthma - the strength of the species rat. Curr Drug Targets. 2008;9:466-9.

26. Redman TK, Rudolph K, Barr EB, Bowen LE, Muggenburg BA, Bice DE. Pulmonary immunity to ragweed in a Beagle dog model of allergic asthma. Exp Lung Res. 2001;27:433-51.

27. Keir S, Page C. The rabbit as a model to study asthma and other lung diseases. Pulm Pharmacol Ther. 2008;21:721-30.

28. Ricciardolo FL, Nijkamp F, De Rose V, Folkerts G. The guinea pig as an animal model for asthma. Curr Drug Targets. 2008;9:452-65.

29. Abraham WM. Modeling of asthma, COPD and cystic fibrosis in sheep. Pulm Pharmacol Ther. 2008;21:743-54.

30. Plopper CG, Hyde DM. The non-human primate as a model for studying COPD and asthma. Pulm Pharmacol Ther. 2008;21:755-66.

31. Shin YS, Takeda K, Gelfand EW. Understanding asthma using animal models. Allergy Asthma Immunol Res. 2009;1:10-8.

32. Mullane K, Williams M. Animal models of asthma: reprise or reboot? Biochem Pharmacol. 2014;87:131-9.

33. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol. 2006;6:476-83.

34. Gill MA. The role of dendritic cells in asthma. J Allergy Clin Immunol. 2012;129:889-901.

35. Shi JH, Lin YG, Li TS. The roles of dendritic cells in antigen presentation and the pathogenesis of asthma. Zhonghua Jie He He Hu Xi Za Zhi. 2005;28:22-7.