Loss of Myeloid Related Protein-8/14 Exacerbates Cardiac Allograft Rejection
Authors: Koichi Shimizu, Peter Libby, Viviane Z. Rocha, Eduardo J. Folco, Rica Shubiki, Nir Grabie, Sunyoung Jang, Andrew H. Lichtman, Ayako Shimizu, Nancy Hogg, Daniel I. Simon, Richard N. Mitchell, Kevin Croce
Journal: Circulation (2011)

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 &gt;12 weeks (n=15; P &lt;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 &lt;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±0.7×10 5 for MRP-14 −/− versus 6.0±0.2×10 5 for WT; P &lt;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.