HCA2 Receptors in Lymphocytes and Keratinocytes Affect Murine Contact Allergic Inflammation

The hydroxycarboxylic acid receptor HCA2 is expressed in keratinocytes and immune cells. In mice, the anti-inflammatory potential of HCA2 receptor signalling in the skin was first described in experimental models of psoriasis-like inflammation and bullous pemphigoid-like epidermolysis bullosa acquisita. We examined contact allergic immune responses to the obligate contact sensitiser DNFB in Hcar2^-/- and wild-type C57BL/6 mice. Basal mRNA levels of pro-inflammatory mediators like IFNγ were already increased in the ear tissue of naïve Hcar2^-/- animals. After sensitisation and challenge with DNFB, contact allergic ear swelling and infiltration of neutrophils and CD3+ T cells were increased in Hcar2^-/- mice. To investigate the impact of HCA2 receptors on T cells, we performed in vitro co-stimulation assays with allergen-loaded dendritic cells and antigen-specific T cells, showing increased proliferation and IFNγ production of Hcar2^-/- T lymphocytes. Adoptive transfer of sensitised lymphocytes and experiments with bone marrow chimeric mice indicated that HCAR2 exerts its anti-inflammatory effect in part through radio-resistant, skin-resident cells in the challenge phase. As a potential mechanism, we found that Hcar2^-/- keratinocytes produced higher levels of the neutrophil-attracting chemokine CCL8. In summary, we show that HCA2 receptors are functionally expressed in lymphocytes and keratinocytes and participate in the attenuation of contact allergic immune responses. Our data indicate that the dominant anti-inflammatory effect of HCA2 signalling during the elicitation phase resides in radio-resistant, skin-resident cells, whereas effects on lymphocyte activation are likely to be modulatory. The precise contribution of distinct skin-resident cell populations and the role of endogenous ligands driving HCA2 signalling in this context remain unresolved.