Abstract
Brain-derived neurotrophic factor (BDNF) enhances periodontal tissue regeneration. Tissue regeneration is characterized by inflammation, which directs the quality of tissue repair. This study aimed to investigate the effect of BDNF on the phagocytic activity of RAW264.7 cells. In addition, we studied the effect of BDNF on guanosine triphosphatase (GTP)-RAS-related C3 botulinus toxin substrate (Rac)1 and phospho-Rac1 levels in RAW264.7 cells. Rac1 inhibitor inhibited BDNF-induced phagocytosis of latex-beads. In addition, BDNF enhanced Porphyromonas gingivalis (Pg) phagocytosis by RAW264.7 cells as well as latex-beads. We demonstrated for the first time that BDNF enhances phagocytic activity of RAW264.7 cells through Rac1 activation. The present study proposes that BDNF may reduce inflammatory stimuli during BDNF-induced periodontal tissue regeneration through enhanced phagocytic activity of macrophages.
Similar content being viewed by others
References
Pihlstrom BL, Michalowicz BS, Johnson NW (2005) Periodontal diseases. Lancet 366:1809–1820
Trindade F, Oppenheim FG, Helmerhorst EJ, Amado F, Gomes PS, Vitorino R (2014) Uncovering the molecular networks in periodontitis. Proteom Clin Appl 8:748–761
Bosshardt DD, Sculean A (2000) Does periodontal tissue regeneration really work? Periodontol 2009(51):208–219
Barbacid M (1994) The Trk family of neurotrophin receptors. J Neurobiol 25:1386–1403
Ebendal T (1992) Function and evolution in the NGF family and its receptors. J Neurosci Res 32:461–470
Johnson D, Lanahan A, Buck CR, Sehgal A, Morgan C, Mercer E et al (1986) Expression and structure of the human NGF receptor. Cell 47:545–554
Patapoutian A, Reichardt LF (2001) Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 11:272–280
Kajiya M, Shiba H, Fujita T, Ouhara K, Takeda K, Mizuno N et al (2008) Brain-derived neurotrophic factor stimulates bone/cementum-related protein gene expression in cementoblasts. J Biol Chem 283:16259–16267
Kajiya M, Shiba H, Fujita T, Takeda K, Uchida Y, Kawaguchi H et al (2009) Brain-derived neurotrophic factor protects cementoblasts from serum starvation-induced cell death. J Cell Physiol 221:696–706
Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE et al (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870
Nakahashi T, Fujimura H, Altar CA, Li J, Kambayashi J, Tandon NN et al (2000) Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett 470:113–117
Nakanishi T, Takahashi K, Aoki C, Nishikawa K, Hattori T, Taniguchi S (1994) Expression of nerve growth factor family neurotrophins in a mouse osteoblastic cell line. Biochem Biophys Res Commun 198:891–897
Takeda K, Shiba H, Mizuno N, Hasegawa N, Mouri Y, Hirachi A et al (2005) Brain-derived neurotrophic factor enhances periodontal tissue regeneration. Tissue Eng 11:1618–1629
Takeda K, Sakai N, Shiba H, Nagahara T, Fujita T, Kajiya M et al (2011) Characteristics of high-molecular-weight hyaluronic acid as a brain-derived neurotrophic factor scaffold in periodontal tissue regeneration. Tissue Eng Part A 17:955–967
Jimbo R, Tovar N, Janal MN, Mousa R, Marin C, Yoo D et al (2014) The effect of brain-derived neurotrophic factor on periodontal furcation defects. PLoS ONE 9:e84845
Sasaki S, Takeda K, Takewaki M, Ouhara K, Kajiya M, Mizuno N et al (2019) BDNF/HMW-HA complex as an adjunct to nonsurgical periodontal treatment of ligature-induced periodontitis in dogs. J Periodontol 90:98–109
Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 127:514–525
Diegelmann RF, Evans MC (2004) Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 9:283–289
Arango Duque G, Descoteaux A (2014) Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 5:491
Chang F, Lemmon C, Lietha D, Eck M, Romer L (2011) Tyrosine phosphorylation of Rac1: a role in regulation of cell spreading. PLoS ONE 6:e28587
Briancon-Marjollet A, Ghogha A, Nawabi H, Triki I, Auziol C, Fromont S et al (2008) Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance. Mol Cell Biol 28:2314–2323
Hordijk PL (2006) Regulation of NADPH oxidases: the role of Rac proteins. Circ Res 98:453–462
Kissil JL, Walmsley MJ, Hanlon L, Haigis KM, Bender Kim CF, Sweet-Cordero A et al (2007) Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res 67:8089–8094
Nikolova E, Mitev V, Zhelev N, Deroanne CF, Poumay Y (2007) The small Rho GTPase Rac1 controls normal human dermal fibroblasts proliferation with phosphorylation of the oncoprotein c-myc. Biochem Biophys Res Commun 359:834–839
Ridley AJ (2006) Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16:522–529
Roepstorff K, Rasmussen I, Sawada M, Cudre-Maroux C, Salmon P, Bokoch G et al (2008) Stimulus-dependent regulation of the phagocyte NADPH oxidase by a VAV1, Rac1, and PAK1 signaling axis. J Biol Chem 283:7983–7993
Tzima E (2006) Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response. Circ Res 98:176–185
Mao Y, Finnemann SC (2015) Regulation of phagocytosis by Rho GTPases. Small GTPases 6:89–99
Takeda K, Tokunaga N, Aida Y, Kajiya M, Ouhara K, Sasaki S et al (2017) Brain-derived neurotrophic factor inhibits peptidoglycan-induced inflammatory cytokine expression in human dental pulp cells. Inflammation 40:240–247
Asami T, Ito T, Fukumitsu H, Nomoto H, Furukawa Y, Furukawa S (2006) Autocrine activation of cultured macrophages by brain-derived neurotrophic factor. Biochem Biophys Res Commun 344:941–947
Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635
Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269
Myers KR, Casanova JE (2008) Regulation of actin cytoskeleton dynamics by Arf-family GTPases. Trends Cell Biol 18:184–192
Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 29:356–370
Grunicke HH (2009) Coordinated regulation of Ras-, Rac-, and Ca2+-dependent signaling pathways. Crit Rev Eukaryot Gene Expr 19:139–169
Del Pozo MA, Schwartz MA (2007) Rac, membrane heterogeneity, caveolin and regulation of growth by integrins. Trends Cell Biol 17:246–250
Schwarz J, Proff J, Havemeier A, Ladwein M, Rottner K, Barlag B et al (2012) Serine-71 phosphorylation of Rac1 modulates downstream signaling. PLoS ONE 7:e44358
Kwon T, Kwon DY, Chun J, Kim JH, Kang SS (2000) Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1. J Biol Chem 275:423–428
Schoentaube J, Olling A, Tatge H, Just I, Gerhard R (2009) Serine-71 phosphorylation of Rac1/Cdc42 diminishes the pathogenic effect of Clostridium difficile toxin A. Cell Microbiol 11:1816–1826
Hurme M, Viherluoto J, Nordstrom T (1992) The effect of calcium mobilization on LPS-induced IL-1 beta production depends on the differentiation stage of the monocytes/macrophages. Scand J Immunol 36:507–511
Liu YC, Lerner UH, Teng YT (2000) Cytokine responses against periodontal infection: protective and destructive roles. Periodontol 2010(52):163–206
Tajima K, Akanuma S, Matsumoto-Akanuma A, Yamanaka D, Ishibashi KI, Adachi Y et al (2018) Activation of macrophages by a laccase-polymerized polyphenol is dependent on phosphorylation of Rac1. Biochem Biophys Res Commun 495:2209–2213
Acknowledgements
This work was supported by JSPS KAKENHI Grants JP25463218 [Grant-in-Aid for scientific Reserch (C)]. We thank the Analysis Center of Life Science of Hiroshima University for the use of facilities.
Author information
Authors and Affiliations
Contributions
All authors equally contributed and gave their final approval to the submitted manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors of the paper declare that there are no conflicts of interest.
Research involving human and animal rights
This article contains no human or animal subjects performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sasaki, S., Takeda, K., Ouhara, K. et al. Involvement of Rac1 in macrophage activation by brain-derived neurotrophic factor. Mol Biol Rep 48, 5249–5257 (2021). https://doi.org/10.1007/s11033-021-06531-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-021-06531-6