AUTHOR=Bin Sofia , Cantarelli Chiara , Horwitz Julian K. , Gentile Micaela , Podestà Manuel Alfredo , La Manna Gaetano , Heeger Peter S. , Cravedi Paolo 

TITLE=Endogenous erythropoietin has immunoregulatory functions that limit the expression of autoimmune kidney disease in mice

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1195662

DOI=10.3389/fimmu.2023.1195662

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Administration of recombinant erythropoietin (EPO), a kidney-produced hormone with erythropoietic functions, has been shown to have multiple immunoregulatory effects in mice and humans, but whether physiological levels of EPO regulate immune function <italic>in vivo</italic> has not been previously evaluated.</p></sec><sec><title>Methods</title><p>We generated mice in which we could downregulate EPO production using a doxycycline (DOX)-inducible, EPO-specific silencing RNA (shEPOrtTA<sup>POS</sup>), and we crossed them with B6.MRL-Fas<sup>lpr</sup>/J mice that develop spontaneous lupus. We treated these B6.MRL/lpr shEPOrtTA<sup>POS</sup> with DOX and serially measured anti-dsDNA antibodies, analyzed immune subsets by flow cytometry, and evaluated clinical signs of disease activity over 6 months of age in B6.MRL/lpr shEPOrtTA<sup>POS</sup> and in congenic shEPOrtTA<sup>NEG</sup> controls.</p></sec><sec><title>Results</title><p>In B6.MRL/lpr mice, <italic>Epo</italic> downregulation augmented anti-dsDNA autoantibody levels and increased disease severity and percentages of germinal center B cells compared with controls. It also increased intracellular levels of IL-6 and MCP-1 in macrophages.</p></sec><sec><title>Discussion</title><p>Our data in a murine model of lupus document that endogenous EPO reduces T- and B-cell activation and autoantibody production, supporting the conclusion that EPO physiologically acts as a counterregulatory mechanism to control immune homeostasis.</p></sec>