Objective: Macrophage is involved in the pathogenesis of I/R injury and allograft rejection. However, the mechanisms underlying this is vastly unknown. This study aims to identify the role of macrophage derived endoplasmic reticulum (ER) stress sensor IRE1α in renal allograft rejection.

Methods: BALB/c kidneys were transplanted into bi-nephrectomized macrophage-specific IRE1α knockout (KO) B6 mice or their wildtype (WT) littermate. Graft survival and renal function were monitored until death or POD120. Rejection is confirmed by histology. Flow cytometry was performed to phenotype graft infiltrating cells. RNAseq and qPCR were used to analyze gene profile.

Results: WT renal allografts recruited host monocyte-macrophages as early as at POD2, with an increased gene expression of the ER stress inducer BiP and its downstream XBP1s, as well as macrophage activation markers, MIP-1γ and CD68. The WT recipients succumbed to renal failure within 60 days due to severe rejection. In contrast, majority of the KO allografts survived >120 days, with minimal cellular infiltration, better renal function and intact renal structure. To determine the effect of macrophage depletion of IRE1α in early phase of transplantation, phenotypical analysis were performed on the graft infiltrating cells at POD2-14. IRE1α depletion did not impair the early recruitment and activation of macrophage. Similar numbers and activation phenotypes (CCR2⁺CD86^hiMHCII^hi) of infiltrating macrophages were observed at POD2 and 6 in both WT and KO allografts. Interestingly, macrophage expression of Mer tyrosine kinase receptor (MerTK) and M2 marker CD206 were significantly upregulated in KO allograft. This correlates with the subsequent resolution of acute rejection in KO allografts by POD14. At POD90, recipient-derived macrophage in KO mice converted to renal resident macrophage with similar phenotype as in naïve kidney.

Conclusions: These data support that ER stress sensor IRE1α deficiency promotes macrophage polarization and renal allograft acceptance. Given the important role of MerTK in efferocytosis and tissues repair, the data suggest that renal allograft protection by macrophage IRE1α depletion may be attributed to the enhanced efferocytosis and tissue repair, linking the ER stress response to efferocytosis pathways.

CITATION INFORMATION: Qiu L., Wang J-.J., Yeap X., Fang D., Zhang J. Endoplasmic Reticulum Stress Sensor IRE1α Deficiency Promotes Infiltrating Macrophage Polarization and Induces Long-Term Renal Allograft Acceptance in Mice Am J Transplant. 2017;17 (suppl 3).

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