Role of CD47 in regulating macrophage and dendritic cell uptake of calcium-induced experimentally senescent erythrocytes in vitro and in vivo

• During senescence, erythrocytes are rapidly eliminated by phagocytes in the spleen and liver,and the interplay between macrophages or dendritic cells (DCs) with lymphocytes in the spleen could be of importance to regulate self-tolerance and to prevent development of autoimmune hemolytic anemia (AIHA).The cell surface glycoprotein CD47 on the surface of host target cells can inhibit phagocytosis of normal circulating blood cells by binding to signal regulatory protein alpha (SIRPα) on macrophages and DCs. Here we investigated the clearance of Ca2+-ionophore-treated experimentally senescent erythrocytes (Ca2+-RBCs) in vivo, and if CD47 on Ca2+-RBCs regulated their uptake by macrophages in vitro or their clearance in vivo. Ca2+-RBCs exposed phosphatidylserine (PS) on their surface and were rapidly phagocytosed by macrophages in vitro. This uptake was dependent on heat-stable serum factors, but was not inhibited by CD47 on the erythrocytes. Following intravenous injection, a large fraction of PKH26-labeled Ca2+-RBCs were trapped by splenic marginal zone macrophages and DCs within 1 hour. In addition, at 20 hours after injection fluorescence from the injected cells could also be detected within the T cell area of the splenic white pulp and associated with both CD8+ and CD8- DCs. We found that DCs in wild-type (Wt) recipient mice showed equal uptake of transfused Wt and CD47-/- Ca2+-RBCs. DCs which had taken up Ca2+-RBCs showed a slight increase in expression levels of CD40, CD86 and MHC class II. In recipients of CD47-/- Ca2+-RBCs, DCs negative for RBC-uptake showed strongly increased expression of CD86, as compared with that in recipients of Wt Ca2+-RBCs. These findings suggest that PS+ erythrocytes may be recognized by splenic macrophages and DCs in ways similar to that reported for nucleated apoptotic cells. Uptake of senescent erythrocytes by DCs may serve as an important mechanism to maintain self-tolerance to erythrocyte antigens, and defects in this function may facilitate development of AIHA.

Subject headings

NATURVETENSKAP  -- Biologi -- Immunologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Immunology (hsv//eng)

Keyword

Immunology

Immunologi

immunologi

Immunology

Publication and Content Type

vet (subject category)

ovr (subject category)