Mast cells are immune sentinels in the skin that respond to a wide range of pathological and environmental stimuli; they owe their function to the expression of Toll-like receptors (TLRs). We previously found that tonsil-derived mesenchymal stem cells (T-MSCs) were able to effectively attenuate TLR7-mediated skin inflammation in mice, which was accompanied by an increase in mast cell number. The present study investigated whether T-MSC extracellular vesicles, such as exosomes, are able to regulate mast cell activation in response to TLR7 stimulation.
The HMC-1 human mast cell line was treated with a TLR7 agonist in the presence or absence of T-MSC exosomes, and the levels of expressed inflammatory cytokines were assessed. Additionally, mice were repeatedly injected with a TLR7 agonist with or without interval treatments with T-MSC exosomes and assessed dermal distribution of mast cells and related immune cells.
We showed that T-MSC exosomes containing microRNAs that target inflammatory cytokines significantly reduced the expression of inflammatory cytokines in TLR7 agonist-treated HMC-1 cells. In addition, T-MSC exosomes inhibited the increase in the number of both dermal mast cells and CD14-positive cells in TLR7 agonist-treated mice.
Our data suggest that T-MSC exosomes have regulatory effects on mast cell activation under inflammatory conditions, including TLR7 stimulation.
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Yu Y, Blokhuis BR, Garssen J, Redegeld FA. Non-IgE mediated mast cell activation. Eur J Pharmacol. 2016;778:33–43.
Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol. 2004;4:787–99.
Lai CY, Su YW, Lin KI, Hsu LC, Chuang TH. Natural modulators of endosomal toll-like receptor-mediated psoriatic skin inflammation. J Immunol Res. 2017;2017:7807313.
Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010;13:1460–2.
Liu T, Gao YJ, Ji RR. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull. 2012;28:131–44.
Lou F, Sun Y, Xu Z, Niu L, Wang Z, Deng S, et al. Excessive polyamine generation in keratinocytes promotes self-RNA sensing by dendritic cells in psoriasis. Immunity. 2020;53:204-16.e10.
Lee EK, Chung KW, Kim YR, Ha S, Kim SD, Kim DH, et al. Small RNAs induce the activation of the pro-inflammatory TLR7 signaling pathway in aged rat kidney. Aging Cell. 2017;16:1026–34.
Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S, et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med. 2005;202:1131–9.
Roers A, Hiller B, Hornung V. Recognition of endogenous nucleic acids by the innate immune system. Immunity. 2016;44:739–54.
Cho KA, Park M, Kim YH, Woo SY. Th17 cell-mediated immune responses promote mast cell proliferation by triggering stem cell factor in keratinocytes. Biochem Biophys Res Commun. 2017;487:856–61.
Kim JY, Park M, Kim YH, Ryu KH, Lee KH, Cho KA, et al. Tonsil-derived mesenchymal stem cells (T-MSCs) prevent Th17-mediated autoimmune response via regulation of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway. J Tissue Eng Regen Med. 2018;12:e1022–33.
Kim YH, Cho KA, Lee HJ, Park M, Shin SJ, Park JW, et al. Conditioned medium from human tonsil-derived mesenchymal stem cells enhances bone marrow engraftment via endothelial cell restoration by pleiotrophin. Cells. 2020;9:221.
Joo HM, Kang SJ, Nam SY, Yang KH, Kim CS, Lee IK, et al. The inhibitory effects of low-dose ionizing radiation in IgE-mediated allergic responses. PLoS One. 2015;10:e0136394.
DeForge LE, Remick DG. Kinetics of TNF, IL-6, and IL-8 gene expression in LPS-stimulated human whole blood. Biochem Biophys Res Commun. 1991;174:18–24.
Weber A, Knop J, Maurer M. Pattern analysis of human cutaneous mast cell populations by total body surface mapping. Br J Dermatol. 2003;148:224–8.
Kim MS, Kim YK, Lee DH, Seo JE, Cho KH, Eun HC, et al. Acute exposure of human skin to ultraviolet or infrared radiation or heat stimuli increases mast cell numbers and tryptase expression in human skin in vivo. Br J Dermatol. 2009;160:393–402.
Gupta K, Harvima IT. Mast cell-neural interactions contribute to pain and itch. Immunol Rev. 2018;282:168–87.
Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010;10:440–52.
Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol. 2015;109:14.12.1-10.
Zhang Z, Ohto U, Shibata T, Krayukhina E, Taoka M, Yamauchi Y, et al. Structural analysis reveals that toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity. 2016;45:737–48.
Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206:1983–94.
Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6:823–35.
Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdörfer B, Giese T, et al. Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531–7.
Edwards AD, Diebold SS, Slack EM, Tomizawa H, Hemmi H, Kaisho T, et al. Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol. 2003;33:827–33.
Barr TA, Brown S, Ryan G, Zhao J, Gray D. TLR-mediated stimulation of APC: distinct cytokine responses of B cells and dendritic cells. Eur J Immunol. 2007;37:3040–53.
Tengroth L, Millrud CR, Kvarnhammar AM, Kumlien Georen S, Latif L, Cardell LO. Functional effects of Toll-like receptor (TLR)3, 7, 9, RIG-I and MDA-5 stimulation in nasal epithelial cells. PLoS One. 2014;9:e98239.
Li ZJ, Sohn KC, Choi DK, Shi G, Hong D, Lee HE, et al. Roles of TLR7 in activation of NF-kappaB signaling of keratinocytes by imiquimod. PLoS ONE. 2013;8:e77159.
Massey VL, Qin L, Cabezas J, Caballeria J, Sancho-Bru P, Bataller R, et al. TLR7-let-7 Signaling contributes to ethanol-induced hepatic inflammatory response in mice and in alcoholic hepatitis. Alcohol Clin Exp Res. 2018;42:2107–22.
Yang H, Wei J, Zhang H, Lin L, Zhang W, He S. Upregulation of Toll-like receptor (TLR) expression and release of cytokines from P815 mast cells by GM-CSF. BMC Cell Biol. 2009;10:37.
Agier J, Brzezińska-Błaszczyk E, Witczak P, Kozłowska E, Żelechowska P. The impact of TLR7 agonist R848 treatment on mast cell phenotype and activity. Cell Immunol. 2021;359:104241.
Witczak P, Pietrzak A, Wódz K, Brzezińska-Błaszczyk E. Mast cells generate cysteinyl leukotrienes and interferon-beta as well as evince impaired IgE-dependent degranulation upon TLR7 engagement. Indian J Exp Biol. 2014;52:589–96.
Kulka M, Alexopoulou L, Flavell RA, Metcalfe DD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol. 2004;114:174–82.
Cho KA, Lee JK, Kim YH, Park M, Woo SY, Ryu KH. Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner. Cell Mol Immunol. 2017;14:895–908.
Cho KA, Park M, Kim YH, Ryu KH, Woo SY. Poly I:C primes the suppressive function of human palatine tonsil-derived MSCs against Th17 differentiation by increasing PD-L1 expression. Immunobiology. 2017;222:394–8.
Casado-Díaz A, Quesada-Gómez JM, Dorado G. Extracellular vesicles derived from mesenchymal stem cells (MSC) in regenerative medicine: applications in skin wound healing. Front Bioeng Biotechnol. 2020;8:146.
Hu P, Yang Q, Wang Q, Shi C, Wang D, Armato U, et al. Mesenchymal stromal cells-exosomes: a promising cell-free therapeutic tool for wound healing and cutaneous regeneration. Burns Trauma. 2019;7:38.
Wu P, Zhang B, Shi H, Qian H, Xu W. MSC-exosome: a novel cell-free therapy for cutaneous regeneration. Cytotherapy. 2018;20:291–301.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIT) (Nos. NRF-2020R1C1C1012769 and NRF-2021R1A2C1012551).
Conflicts of interest
The authors declare that they have no conflict of interest.
The animal studies were performed after receiving approval of the Institutional Animal Care and Use Committee (IACUC) in Ewha Woman’s University, College of Medicine (EUM 20-024).
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Cho, KA., Cha, JE., Kim, J. et al. Mesenchymal Stem Cell-Derived Exosomes Attenuate TLR7-Mediated Mast Cell Activation. Tissue Eng Regen Med (2021). https://doi.org/10.1007/s13770-021-00395-4
- Mast cell
- Mesenchymal stem cell