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A20 inhibition of STAT1 expression in myeloid cells : a novel endogenous regulatory mechanism preventing development of enthesitis

Katelijne De Wilde (UGent) , Arne Martens, Stijn Lambrecht (UGent) , Peggy Jacques (UGent) , Michael Drennan (UGent) , Karlijn Debusschere (UGent) , Srinath Govindarajan (UGent) , Julie Coudenys (UGent) , Eveline Verheugen (UGent) , Fien Windels (UGent) , et al.
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Abstract
Objectives: A20 is an important endogenous regulator of inflammation. Single nucleotide polymorphisms in A20 have been associated with various immune-mediated inflammatory diseases, and cell-specific deletion of A20 results in diverse inflammatory phenotypes. Our goal was to delineate the underlying mechanisms of joint inflammation in myeloid-specific A20-deficient mice (A20(myelKO) mice). Methods: Inflammation in A20(myelKO) mice was assessed in a time-dependent manner. Western blot analysis and quantitative PCR analysis were performed on bone marrow-derived macrophages from A20(myelKO) and littermate control mice to study the effect of A20 on STAT1/STAT3 expression and STAT1/STAT3-dependent gene transcription in myeloid cells. The in vivo role of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling in the development of enthesitis in A20(myelKO) mice was assessed following administration of a JAK inhibitor versus placebo control. Results: Enthesitis was found to be an early inflammatory lesion in A20(myelKO) mice. A20 negatively modulated STAT1-dependent, but generally not STAT3-dependent gene transcription in myeloid cells by suppressing STAT1 but not STAT3 expression, both in unstimulated conditions and after interferon-gamma. or interleukin-6 stimulation. The increase in STAT1 gene transcription in the absence of A20 was shown to be JAK-STAT-dependent. Moreover, JAK inhibition in vivo resulted in significant reduction of enthesitis, both clinically and histopathologically. Conclusions: Our data reveal an important and novel interplay between myeloid cells and tissue resident cells at entheseal sites that is regulated by A20. In the absence of A20, STAT1 but not STAT3 expression is enhanced leading to STAT1-dependent inflammation. Therefore, A20 acts as a novel endogenous regulator of STAT1 that prevents onset of enthesitis.
Keywords
NF-KAPPA-B, SYNOVIO-ENTHESEAL COMPLEX, RHEUMATOID-ARTHRITIS, INFLAMMATION, IMMUNITY, IDENTIFICATION, DISEASE

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MLA
De Wilde, Katelijne et al. “A20 Inhibition of STAT1 Expression in Myeloid Cells : a Novel Endogenous Regulatory Mechanism Preventing Development of Enthesitis.” ANNALS OF THE RHEUMATIC DISEASES 76.3 (2017): 585–592. Print.
APA
De Wilde, Katelijne, Martens, A., Lambrecht, S., Jacques, P., Drennan, M., Debusschere, K., Govindarajan, S., et al. (2017). A20 inhibition of STAT1 expression in myeloid cells : a novel endogenous regulatory mechanism preventing development of enthesitis. ANNALS OF THE RHEUMATIC DISEASES, 76(3), 585–592.
Chicago author-date
De Wilde, Katelijne, Arne Martens, Stijn Lambrecht, Peggy Jacques, Michael Drennan, Karlijn Debusschere, Srinath Govindarajan, et al. 2017. “A20 Inhibition of STAT1 Expression in Myeloid Cells : a Novel Endogenous Regulatory Mechanism Preventing Development of Enthesitis.” Annals of the Rheumatic Diseases 76 (3): 585–592.
Chicago author-date (all authors)
De Wilde, Katelijne, Arne Martens, Stijn Lambrecht, Peggy Jacques, Michael Drennan, Karlijn Debusschere, Srinath Govindarajan, Julie Coudenys, Eveline Verheugen, Fien Windels, Leen Catrysse, Rik Lories, Dennis McGonagle, Rudi Beyaert, Geert van Loo, and Dirk Elewaut. 2017. “A20 Inhibition of STAT1 Expression in Myeloid Cells : a Novel Endogenous Regulatory Mechanism Preventing Development of Enthesitis.” Annals of the Rheumatic Diseases 76 (3): 585–592.
Vancouver
1.
De Wilde K, Martens A, Lambrecht S, Jacques P, Drennan M, Debusschere K, et al. A20 inhibition of STAT1 expression in myeloid cells : a novel endogenous regulatory mechanism preventing development of enthesitis. ANNALS OF THE RHEUMATIC DISEASES. 2017;76(3):585–92.
IEEE
[1]
K. De Wilde et al., “A20 inhibition of STAT1 expression in myeloid cells : a novel endogenous regulatory mechanism preventing development of enthesitis,” ANNALS OF THE RHEUMATIC DISEASES, vol. 76, no. 3, pp. 585–592, 2017.
@article{8166110,
  abstract     = {Objectives: A20 is an important endogenous regulator of inflammation. Single nucleotide polymorphisms in A20 have been associated with various immune-mediated inflammatory diseases, and cell-specific deletion of A20 results in diverse inflammatory phenotypes. Our goal was to delineate the underlying mechanisms of joint inflammation in myeloid-specific A20-deficient mice (A20(myelKO) mice). 
Methods: Inflammation in A20(myelKO) mice was assessed in a time-dependent manner. Western blot analysis and quantitative PCR analysis were performed on bone marrow-derived macrophages from A20(myelKO) and littermate control mice to study the effect of A20 on STAT1/STAT3 expression and STAT1/STAT3-dependent gene transcription in myeloid cells. The in vivo role of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling in the development of enthesitis in A20(myelKO) mice was assessed following administration of a JAK inhibitor versus placebo control. 
Results: Enthesitis was found to be an early inflammatory lesion in A20(myelKO) mice. A20 negatively modulated STAT1-dependent, but generally not STAT3-dependent gene transcription in myeloid cells by suppressing STAT1 but not STAT3 expression, both in unstimulated conditions and after interferon-gamma. or interleukin-6 stimulation. The increase in STAT1 gene transcription in the absence of A20 was shown to be JAK-STAT-dependent. Moreover, JAK inhibition in vivo resulted in significant reduction of enthesitis, both clinically and histopathologically. 
Conclusions: Our data reveal an important and novel interplay between myeloid cells and tissue resident cells at entheseal sites that is regulated by A20. In the absence of A20, STAT1 but not STAT3 expression is enhanced leading to STAT1-dependent inflammation. Therefore, A20 acts as a novel endogenous regulator of STAT1 that prevents onset of enthesitis.},
  author       = {De Wilde, Katelijne and Martens, Arne and Lambrecht, Stijn and Jacques, Peggy and Drennan, Michael and Debusschere, Karlijn and Govindarajan, Srinath and Coudenys, Julie and Verheugen, Eveline and Windels, Fien and Catrysse, Leen and Lories, Rik and McGonagle, Dennis and Beyaert, Rudi and van Loo, Geert and Elewaut, Dirk},
  issn         = {0003-4967},
  journal      = {ANNALS OF THE RHEUMATIC DISEASES},
  keywords     = {NF-KAPPA-B,SYNOVIO-ENTHESEAL COMPLEX,RHEUMATOID-ARTHRITIS,INFLAMMATION,IMMUNITY,IDENTIFICATION,DISEASE},
  language     = {eng},
  number       = {3},
  pages        = {585--592},
  title        = {A20 inhibition of STAT1 expression in myeloid cells : a novel endogenous regulatory mechanism preventing development of enthesitis},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2016-209454},
  volume       = {76},
  year         = {2017},
}

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