Splenic MARCO+ marginal zone macrophages regulate rapid production of MCP-1 and KC but are dispensable for alloantibody generation in response to stored RBCs in a murine model.

Abstract

BACKGROUNDAlloimmunization to transfused red blood cells (RBCs) remains a significant clinical problem. However, the cells that initiate immune responses to transfused RBCs remain incompletely characterized. Recently published work has identified splenic marginal zone B (MZB) cells as being critically required for the production of anti-RBC alloantibodies in response to RBCs. In infectious models, MZB cell activation has been shown to depend on a unique population of marginal zone macrophages (MZMs). We hypothesized that MZMs would capture stored RBCs and present them to MZBs, and ultimately MZMs would be required for generation of anti-RBC alloantibodies in response to stored RBC transfusion. STUDY DESIGN AND METHODSStored GFP+ murine RBCs were utilized to determine the splenic localization and erythrophagocytosis by splenic macrophage populations. To determine the functional impact of MZMs, we compared LXR-KO mice, which have been reported to lack MZMs, with wild type mice. Both innate and adaptive immune responses to stored HOD allogenic RBC transfusion were measured in LXR-KO and wild type mice. RESULTSRBC storage leads to a significant increase in the phagocytosis of transfused RBCs by splenic MZMs. LXR-KO mice demonstrated a lack of MZMs and had significantly decreased rapid phase production of cytokines MCP-1 and KC, but similar levels of IL-6. Surprisingly, anti-RBC alloantibody levels were unaffected by the absence of splenic MZMs. CONCLUSIONSSplenic MZMs are involved in the innate response to transfused stored HOD RBCs, contributing to both MCP-1 and KC cytokine production. However, MZMs are dispensable for anti-RBC alloantibody production.