Adenosine A2A Receptor Activation Alleviated Disease of Mice with Systemic Candida albicans Infection by Regulating Macrophage Function

Xia-nan Wu,* Ke Dong,* Yan Liu, Lan Yang, Jing Zhang, Ming Yang, Zhao-wei Gao Department of Clinical Laboratory, Tangdu Hospital, Airforce Medical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhao-wei Gao, Department of Clinical Laboratory, Tangdu Hospital, Airforce Medical University, Xi’an, Shaanxi, People’s Republic of China, Email [email protected]: The incidence of candidemia, mediated by systemic Candida albicans (C. albicans) infection, was increasing. It is an urgent need to understand the underlying disease mechanisms to identify new therapeutic targets. This study aimed to investigate the roles of adenosine–adenosine receptor signal in systemic C. albicans infection.Methods: The candidemia mice models (named CA mice) were established by tail intravenous injection of C. albicans. CA Mice were treated with NECA (a metabolically stable adenosine analogue) or agonists targeting different adenosine receptors (A1R, A2AR, A2BR and A3R). The survival rate, renal fungal load and tissue damage were investigated. Bone marrow-derived macrophages (BMDM) were isolated and cultured to investigate the effects of NECA and adenosine receptor agonist on phagocytosis, killing function and polarization of macrophages.Results: In CA mice, we observed that NECA and A2AR agonist treatment significantly alleviated the sepsis score and increased the survival rate. Moreover, the renal injury and fungal load were reduced by NECA and A2AR agonist treatment. However, the other adenosine receptors (ie, A1R, A2BR and A3R) activation have no effect on survival and tissue damage of CA mice. A2AR activation could reduce macrophage infiltration in kidney and the production of inflammatory cytokine IL-6 in CA mice. Moreover, adenosine-A2AR signaling activation could enhance antifungal capacity of macrophages and promoted macrophage polarization toward the M2 subtype.Conclusion: Activation of adenosine-A2AR axis promoted macrophage M2 polarization, enhanced host defense against systemic C. albicans infection, and alleviated candidiasis. A2AR activation could be considered as a potential therapeutic strategy in candidemia.Keywords: C. albicans, systemic infection, adenosine receptor, renal injury, macrophage