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Adenosine A2A receptor activation stimulates collagen production in sclerodermic dermal fibroblasts either directly and through a cross-talk with the cannabinoid system

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Abstract

Systemic sclerosis (SSc) is a connective tissue disease characterised by exaggerated collagen deposition in the skin and visceral organs. Adenosine A2A receptor stimulation (A2Ar) promotes dermal fibrosis, while the cannabinoid system modulates fibrogenesis in vitro and in animal models of SSc. Moreover, evidence in central nervous system suggests that A2A and cannabinoid (CB1) receptors may physically and functionally interact. On this basis, we investigated A2Ar expression and function in modulating collagen biosynthesis from SSc dermal fibroblasts and analysed the cross-talk with cannabinoid receptors. In sclerodermic cells, A2Ar expression (RT-PCR, Western blotting) was evaluated together with the effects of A2A agonists and/or antagonists on collagen biosynthesis (EIA, Western blotting). Putative physical and functional interactions between the A2A and cannabinoid receptors were respectively assessed by co-immuno-precipitation and co-incubating the cells with the unselective cannabinoid agonist WIN55,212-2, and the selective A2A antagonist ZM-241385. In SSc fibroblasts, (1) the A2Ar is overexpressed and its occupancy with the selective agonist CGS-21680 increases collagen production, myofibroblast trans-differentiation, and ERK-1/2 phosphorylation; (2) the A2Ar forms an heteromer with the cannabinoid CB1 receptor; and (3) unselective cannabinoid receptor stimulation with a per se ineffective dose of WIN55,212-2, results in a marked anti-fibrotic effect after A2Ar blockage. In conclusion, A2Ar stimulation induces a pro-fibrotic phenotype in SSc dermal fibroblasts, either directly, and indirectly, by activating the CB1 cannabinoid receptor. These findings increase our knowledge of the pathophysiology of sclerodermic fibrosis also further suggesting a new therapeutic approach to the disease.

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Conflict of interests

The authors declare no conflict of interests related to this study.

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Authors and Affiliations

  1. Department of Clinical Medicine and Immunological Sciences, Division of Clinical Immunology, University of Siena, Siena, Italy

    Pietro Enea Lazzerini, Mariarita Natale, Elena Gianchecchi, Pier Leopoldo Capecchi, Cinzia Montilli, Stefania Zimbone, Monica Castrichini, Gianluca Ricci & Franco Laghi-Pasini

  2. Department of Clinical Medicine and Immunological Sciences, Division of Rheumatology, University of Siena, Siena, Italy

    Epifania Balistreri, Enrico Selvi, Estrella Garcia-Gonzalez & Mauro Galeazzi

Authors
  1. Pietro Enea Lazzerini
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  2. Mariarita Natale
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  3. Elena Gianchecchi
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  4. Pier Leopoldo Capecchi
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  5. Cinzia Montilli
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  6. Stefania Zimbone
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  8. Epifania Balistreri
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  9. Gianluca Ricci
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  10. Enrico Selvi
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  11. Estrella Garcia-Gonzalez
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  12. Mauro Galeazzi
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  13. Franco Laghi-Pasini
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Correspondence to Elena Gianchecchi.

Additional information

Pietro Enea Lazzerini, Mariarita Natale, and Elena Gianchecchi are contributed equally to this work.

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Lazzerini, P.E., Natale, M., Gianchecchi, E. et al. Adenosine A2A receptor activation stimulates collagen production in sclerodermic dermal fibroblasts either directly and through a cross-talk with the cannabinoid system. J Mol Med 90, 331–342 (2012). https://doi.org/10.1007/s00109-011-0824-5

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  • DOI: https://doi.org/10.1007/s00109-011-0824-5

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