Herpesvirus entry mediator regulates hypoxia-inducible factor–1α and erythropoiesis in mice

Abstract

Erythropoiesis, the production of red blood cells, must be tightly controlled to ensure adequate oxygen delivery to tissues without causing thrombosis or stroke. Control of physiologic and pathologic erythropoiesis is dependent predominantly on erythropoietin (EPO), the expression of which is regulated by hypoxia-inducible factor (HIF) activity in response to low oxygen tension. Accumulating evidence indicates that oxygen-independent mediators, including inflammatory stimuli, cytokines, and growth factors, also upregulate HIF activity, but it is unclear whether these signals also result in EPO production and erythropoiesis in vivo. Here, we found that signaling through herpesvirus entry mediator (HVEM), a molecule of the TNF receptor superfamily, promoted HIF-1α activity in the kidney and subsequently facilitated renal Epo production and erythropoiesis in vivo under normoxic conditions. This Epo upregulation was mediated by increased production of NO by renal macrophages. Hvem-deficient mice displayed impaired Epo expression and aggravated anemia in response to erythropoietic stress. These data reveal that HVEM signaling functions to promote HIF-1α activity and Epo production, and thus to regulate erythropoiesis. Furthermore, our findings suggest that this molecular mechanism could represent a therapeutic target for Epo-responsive diseases, including anemia.

Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells

“…In this context, it is important to emphasize that a deficiency in CD24 does not affect basal/homeostatic erythropoiesis and only diminishes (or more precisely delays) pathologic stress-induced erythropoiesis. Thus, it is likely that CD24 is only one of several, e.g., herpesvirus entry mediator (HVEM) (40) and acetate (41), stress sensors capable of regulating erythropoiesis in response to stress.…”

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

“…Our data indicated that LBH1 mAb abrogated not only LIGHT-HVEM interaction (18,25) but also BTLA-HVEM interaction (data not shown). Thus, we next examined whether LBH1 treatment ameliorated EAU by interfering with HVEM stimulatory cosignals.…”

“…We previously developed an anti-HVEM mAb clone LBH1 that has antagonistic but not agonistic ability (18,25). Our data indicated that LBH1 mAb abrogated not only LIGHT-HVEM interaction (18,25) but also BTLA-HVEM interaction (data not shown).…”

“…For instance, costimulatory signaling by HVEM could become predominant when it binds LIGHT and BTLA in T cell-T cell interactions (17,18). In addition, ligation of HVEM on macrophages is known to affect functions of these cells (25,42). Thus, it is possible that HVEM mediates stimulatory effects via T cells and/or macrophages, which are both pathogenic to EAU.…”

“…Anti-mouse HVEM mAb (clone HM3.30; hamster IgG) and anti-mouse HVEM antagonistic mAb (clone LBH1; hamster IgG) were generated in our laboratory as previously described (18,25). Fluorochrome-conjugated Abs for flow cytometric analysis were purchased from BD Biosciences (San Diego, CA), eBioscience (San Diego, CA), or BioLegend (San Diego, CA).…”