Loss of Myeloid Related Protein-8/14 Exacerbates Cardiac Allograft Rejection

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Abstract

Background—

The calcium-binding proteins myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) form MRP-8/14 heterodimers (S100A8/A9, calprotectin) that regulate myeloid cell function and inflammatory responses and serve as early serum markers for monitoring acute allograft rejection. Despite functioning as a proinflammatory mediator, the pathophysiological role of MRP-8/14 complexes in cardiovascular disease is incompletely defined. This study investigated the role of MRP-8/14 in cardiac allograft rejection using MRP-14−/− mice that lack MRP-8/14 complexes.

Methods and Results—

We examined parenchymal rejection after major histocompatibility complex class II allomismatched cardiac transplantation (bm12 donor heart and B6 recipients) in wild-type (WT) and MRP-14−/− recipients. Allograft survival averaged 5.9±2.9 weeks (n=10) in MRP-14−/− recipients compared with >12 weeks (n=15; P<0.0001) in WT recipients. Two weeks after transplantation, allografts in MRP-14−/− recipients had significantly higher parenchymal rejection scores (2.8±0.8; n=8) than did WT recipients (0.8±0.8; n=12; P<0.0001). Compared with WT recipients, allografts in MRP-14−/− recipients had significantly increased T-cell and macrophage infiltration and increased mRNA levels of interferon-γ and interferon-γ–associated chemokines (CXCL9, CXCL10, and CXCL11), interleukin-6, and interleukin-17 with significantly higher levels of Th17 cells. MRP-14−/− recipients also had significantly more lymphocytes in the adjacent para-aortic lymph nodes than did WT recipients (cells per lymph node: 23.7±0.7×105 for MRP-14−/− versus 6.0±0.2×105 for WT; P<0.0001). The dendritic cells (DCs) of the MRP-14−/− recipients of bm12 hearts expressed significantly higher levels of the costimulatory molecules CD80 and CD86 than did those of WT recipients 2 weeks after transplantation. Mixed leukocyte reactions with allo–endothelial cell–primed MRP-14−/− DCs resulted in significantly higher antigen-presenting function than reactions using WT DCs. Ovalbumin-primed MRP-14−/− DCs augmented proliferation of OT-II (ovalbumin-specific T cell receptor transgenic) CD4+ T cells with increased interleukin-2 and interferon-γ production. Cardiac allografts of B6 major histocompatibility complex class II−/− hosts and of B6 WT hosts receiving MRP-14−/− DCs had significantly augmented inflammatory cell infiltration and accelerated allograft rejection compared with WT DCs from transferred recipient allografts. Bone marrow–derived MRP-14−/− DCs infected with MRP-8 and MRP-14 retroviral vectors showed significantly decreased CD80 and CD86 expression compared with controls, indicating that MRP-8/14 regulates B7-costimulatory molecule expression.

Conclusions—

Our results indicate that MRP-14 regulates B7 molecule expression and reduces antigen presentation by DCs and subsequent T-cell priming. The absence of MRP-14 markedly increased T-cell activation and exacerbated allograft rejection, indicating a previously unrecognized role for MRP-14 in immune cell biology.

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