Dataset Information

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

ABSTRACT:

Background

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 in vivo has not been previously evaluated.

Methods

We generated mice in which we could downregulate EPO production using a doxycycline (DOX)-inducible, EPO-specific silencing RNA (shEPOrtTA^POS), and we crossed them with B6.MRL-Fas^lpr/J mice that develop spontaneous lupus. We treated these B6.MRL/lpr shEPOrtTA^POS 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^POS and in congenic shEPOrtTA^NEG controls.

Results

In B6.MRL/lpr mice, Epo 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.

Discussion

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.

SUBMITTER: Bin S

PROVIDER: S-EPMC10381939 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

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

Bin Sofia S Cantarelli Chiara C Horwitz Julian K JK Gentile Micaela M Podestà Manuel Alfredo MA La Manna Gaetano G Heeger Peter S PS Cravedi Paolo P

Frontiers in immunology 20230713

<h4>Background</h4>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 <i>in vivo</i> has not been previously evaluated.<h4>Methods</h4>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 cro ...[more]

PMID: 37520571

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Project description:Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the 'extrinsic' pathway, which is triggered by engagement of cell surface 'death receptors' such as Fas/APO-1; and the 'intrinsic' pathway, which is triggered by diverse cellular stresses, and is regulated by pro-survival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the pro-apoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+CD4-CD8-B220+) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types.

Dataset Information

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

Background

Methods

Results

Discussion

Publications

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

Similar Datasets

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