The Role of the Ketone Receptor HCA2 in the Management of Psoriatic Skin Inflammation
The hydroxy-carboxylic acid receptor 2 (HCA2) is a G-protein-coupled receptor for which the ketone β-hydroxybutyrate and the short chain fatty acid butyrate are known agonists. Both are endogenous compounds generated during fatty acid metabolism and by the intestinal microflora, respectively. Nicotinic acid (NA, vitamin B3) is another agonist of HCA2 and high doses of NA are used for the treatment of lipid disorders. Monomethyl fumarate (MMF), the bioactive in vivo metabolite of the prodrug dimethyl fumarate (DMF) was identified as an agonist of the HCA2 receptor. DMF-based therapies have been used in Germany since 1997 for systemic therapy of moderate to severe plaque psoriasis. Although HCA2-mediated effects of NA have been analysed extensively, little is known about the role of HCA2 signalling in the treatment of psoriasis. Despite its long-term use in psoriasis and the identification of HCA2’s role in a common side effect of NA and DMF treatment, flush, the role of HCA2 for the therapeutic effect of oral DMF treatment in psoriasis is not yet known. This work demonstrated that oral DMF treatment in psoriasis patients led to a rapid improvement of psoriasis lesions. The reduction of skin inflammation was accompanied by a decrease in peripheral leukocytes, mainly neutrophils. Neutrophils express HCA2, and it was assumed that the decrease of these cells was mediated by HCA2-dependent mechanisms. The data showed that apoptosis was not induced in neutrophils and can therefore not explain the reduction of this cell type. By using the Imiquimod model of psoriasis-like skin inflammation employing HCA2 expressing and deficient mice, the therapeutic effect of oral DMF treatment was confirmed to be dependent on this receptor. In these experiments oral DMF did not affect immune cells but changed the expression of keratinocyte-derived pro-inflammatory cytokines. Interestingly, mice kept on a ketogenic diet to raise blood β-hydroxybutyrate levels showed less skin inflammation that was independent of HCA2 expression. The use of bone marrow chimeras demonstrated that oral DMF treatment mediated its therapeutic effect through HCA2 expressed by radio-resistant cells, most likely keratinocytes. In vitro analysis showed that MMF treatment reduced the proliferation of keratinocytes. In conclusion, this work showed that the metabolic sensor HCA2 mediated the therapeutic effect of oral DMF on psoriasis skin inflammation by directly affecting the proliferation of keratinocytes.