Oncostatin M upregulates CD73 via the MAPK pathway in keratinocytes to promote an adenosine-dependent anti-inflammatory response in psoriasis

Introduction: Psoriasis is a chronic inflammatory skin condition driven by activated epidermal keratinocytes, dermal fibroblasts, and immune cell infiltrates, which causes tissue injury. The ecto-5′-nucleotidase CD73/adenosine pathway plays a critical role in controlling inflammatory/immune responses, yet it is dysregulated in psoriasis patients. However, the expression and function of this pathway in psoriasis remain poorly explored. Methods: In this study, we investigated the regulation of CD73 in keratinocytes and examined the anti-inflammatory effects of adenosine in keratinocytes and dermal fibroblasts under psoriatic-like conditions. HaCaT cells and primary normal human epidermal keratinocytes (NHEK) were stimulated with the M5 cytokine cocktail, comprising interleukin (IL)-1α, IL-17A, IL-22, oncostatin M (OSM), and tumor necrosis factor (TNF)-α, to induce a proinflammatory phenotype. Results: M5-treated keratinocytes release IL-1β, IL-6, and IL-8, as well as the antimicrobial peptide S100A9, and exhibit activation of the signal transducer and activator of transcription (STAT), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways. We demonstrated that CD73 is upregulated in inflamed keratinocytes, with OSM identified as a regulator of CD73 expression in a Janus kinase/MAPK-dependent manner. High CD73 expression in inflamed keratinocytes is associated with increased adenosine production. In M5-stimulated keratinocytes, adenosine A2A receptors (A2AR) expression is increased, whereas A2BR expression is decreased. Functional analyses revealed that an A2AR agonist, and to a lesser extent an A2BR agonist, reduced IL-8 levels in inflamed keratinocytes. Similarly, M5-treated dermal fibroblasts released IL-1β, IL-6, and IL-8, and exhibited activation of inflammatory signaling pathways. In inflamed dermal fibroblasts, both A2AR and A2BR were upregulated, and IL-8 release was mitigated by an A2AR agonist. Discussion: In conclusion, these results provide new insights into the mechanisms by which the CD73/adenosine axis can be modulated in psoriatic conditions and may guide the development of effective strategies to mitigate inflammation.