MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis

Mariola Kurowska-Stolarska; Stefano Alivernini; Emma Garcia Melchor; Aziza Elmesmari; Barbara Tolusso; Clare Tange; Luca Petricca; Derek S. Gilchrist; Gabriele Di Sante; Chantal Keijzer; Lynn Stewart; Clara Di Mario; Vicky Morrison; James M. Brewer; Duncan Porter; Simon Milling; Ronald D. Baxter; David Mccarey; Elisa Gremese; Greg Lemke; Gianfranco Ferraccioli; Charles Mcsharry; Iain B. Mcinnes

doi:10.1038/ncomms15877

MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis

Mariola Kurowska-Stolarska^*
, Stefano Alivernini
, Emma Garcia Melchor
, Aziza Elmesmari
, Barbara Tolusso
, Clare Tange
, Luca Petricca
, Derek S. Gilchrist
, Gabriele Di Sante
, Chantal Keijzer
, Lynn Stewart
, Clara Di Mario
, Vicky Morrison
, James M. Brewer
, Duncan Porter
, Simon Milling
, Ronald D. Baxter
, David Mccarey
, Elisa Gremese
, Greg Lemke

Gianfranco Ferraccioli, Charles Mcsharry, Iain B. Mcinnes^*

^*Corresponding author

University of Glasgow
NHS Greater Glasgow and Clyde
Salk Institute for Biological Studies

Research output: Contribution to journal › Article

42 Citations (Scopus)

Abstract

Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c + DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c + DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.

Original language	English
Pages (from-to)	15877-15891
Number of pages	15
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15877
Publication status	Published - 2017

Keywords

Biochemistry, Genetics and Molecular Biology (all)
Chemistry (all)
Physics and Astronomy (all)

Access to Document

10.1038/ncomms15877

Cite this

Kurowska-Stolarska, M., Alivernini, S., Melchor, E. G., Elmesmari, A., Tolusso, B., Tange, C., Petricca, L., Gilchrist, D. S., Di Sante, G., Keijzer, C., Stewart, L., Di Mario, C., Morrison, V., Brewer, J. M., Porter, D., Milling, S., Baxter, R. D., Mccarey, D., Gremese, E., ... Mcinnes, I. B. (2017). MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis. Nature Communications, 8, 15877-15891. https://doi.org/10.1038/ncomms15877

@article{ab9acc0672294626a20910495b7882f8,

title = "MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis",

abstract = "Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c + DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c + DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.",

keywords = "Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all)",

author = "Mariola Kurowska-Stolarska and Stefano Alivernini and Melchor, \{Emma Garcia\} and Aziza Elmesmari and Barbara Tolusso and Clare Tange and Luca Petricca and Gilchrist, \{Derek S.\} and \{Di Sante\}, Gabriele and Chantal Keijzer and Lynn Stewart and \{Di Mario\}, Clara and Vicky Morrison and Brewer, \{James M.\} and Duncan Porter and Simon Milling and Baxter, \{Ronald D.\} and David Mccarey and Elisa Gremese and Greg Lemke and Gianfranco Ferraccioli and Charles Mcsharry and Mcinnes, \{Iain B.\}",

year = "2017",

doi = "10.1038/ncomms15877",

language = "English",

volume = "8",

pages = "15877--15891",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Kurowska-Stolarska, M, Alivernini, S, Melchor, EG, Elmesmari, A, Tolusso, B, Tange, C, Petricca, L, Gilchrist, DS, Di Sante, G, Keijzer, C, Stewart, L, Di Mario, C, Morrison, V, Brewer, JM, Porter, D, Milling, S, Baxter, RD, Mccarey, D, Gremese, E, Lemke, G, Ferraccioli, G, Mcsharry, C & Mcinnes, IB 2017, 'MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis', Nature Communications, vol. 8, pp. 15877-15891. https://doi.org/10.1038/ncomms15877

TY - JOUR

T1 - MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis

AU - Kurowska-Stolarska, Mariola

AU - Alivernini, Stefano

AU - Melchor, Emma Garcia

AU - Elmesmari, Aziza

AU - Tolusso, Barbara

AU - Tange, Clare

AU - Petricca, Luca

AU - Gilchrist, Derek S.

AU - Di Sante, Gabriele

AU - Keijzer, Chantal

AU - Stewart, Lynn

AU - Di Mario, Clara

AU - Morrison, Vicky

AU - Brewer, James M.

AU - Porter, Duncan

AU - Milling, Simon

AU - Baxter, Ronald D.

AU - Mccarey, David

AU - Gremese, Elisa

AU - Lemke, Greg

AU - Ferraccioli, Gianfranco

AU - Mcsharry, Charles

AU - Mcinnes, Iain B.

PY - 2017

Y1 - 2017

N2 - Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c + DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c + DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.

AB - Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c + DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c + DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.

KW - Biochemistry, Genetics and Molecular Biology (all)

KW - Chemistry (all)

KW - Physics and Astronomy (all)

KW - Biochemistry, Genetics and Molecular Biology (all)

KW - Chemistry (all)

KW - Physics and Astronomy (all)

UR - http://hdl.handle.net/10807/109601

UR - http://www.nature.com/ncomms/index.html

U2 - 10.1038/ncomms15877

DO - 10.1038/ncomms15877

M3 - Article

SN - 2041-1723

VL - 8

SP - 15877

EP - 15891

JO - Nature Communications

JF - Nature Communications

ER -

MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this