The role of the Cx3CR1-Cx3CL1-axis in the primary adrenal immune answer to sepsis

Moritz Wolfram Leweke1, Sebastian Schwab2, Melanie Eichler1, Christian Kurts1

1 Institute of Experimental Immunology, University of Bonn, Bonn, Germany
2 Institute of Experimental Immunology, University of Bonn, Bonn, Germany/Department of Internal Medicine I, University of Bonn, Bonn, Germany

Introduction Sepsis results from a dysregulated immune response to infection. It often ends in septic shock, presenting with hypotension, disseminated intravascular coagulation and severe organ damage. Even if an optimal therapy is given, sepsis still shows a high lethality rate of 10-60%. The adrenal gland (AG) is a key player for a favourable outcome, as it produces both corticosteroids and catecholamines (CATs). The therapeutic administration of catecholamines is well established, however, the role of glucocorticoids in sepsis is heavily debated, and the the “when” and “how” remains to be investigated. As the production and release of these hormones can be enhanced via inflammatory cytokines produced by macrophages and dendritic cells, we hypothesized that a directed migration of monocytes specifically into the AG in the early stages of sepsis would be beneficial. The Cx3CL1-Cx3CR1 axis is known to be important for the directed monocyte migration, thus making it a promising therapeutic target. Results and Outlook Using FACS, ELISA, rtPCR, and immunohistochemistry we were able to demonstrate a selective dependency of adrenal phagocytes to the Cx3CR1-Cx3CL1 axis. The lack of Cx3CR1 correlated with lowered cell counts in the AG and also slower hormone answer upon challenge. After infection there was a significant infiltration of phagocytes into the adrenal gland. We were able to increase CX3CR1 cell surface expression by in vitro treatment of CD11c+ macrophages and dendritic cells with Dexamethasone. Based on these results, a mechanism for modulation of Cx3CR1 for faster cell migration to increase the AG answer is currently investigated.