*Purpose: A major etiology contributing to poor allograft survival is the inevitable ischemic insult it incurs during transplantation. Macrophages are key players in ischemia-reperfusion injury, however, their potential to be harnessed for their reparative functions is yet to be discovered. Allograft Inflammatory Factor-1 (AIF-1) is expressed primarily in macrophages and has been implicated in chronic heart allograft rejection, but its role in kidney ischemia-reperfusion injury is entirely unknown.

*Methods: Kidneys from AIF-1 KO and WT mice were subjected to unilateral warm ischemia for 30 minutes via a left renal pedicle clamp and contralateral nephrectomy was performed prior to sacrifice. Bone Marrow-Derived Macrophages (BMDM) were cultured using bone marrow cells treated with m-CSF and subsequently stimulated with LPS (100ng/ml) and IFN-γ (20ng/ml).

*Results: Significant upregulation of AIF-1 expression was seen in the kidney after ischemic injury. This correlated positively with the degree of fibrosis and progressing time from the initial injury, up to 28 days. Using flow cytometry, we found that AIF-1 in the kidney was predominantly expressed by infiltrating macrophages. Interestingly, the deficiency of AIF-1 resulted in significantly lowered fibrosis, improved kidney function, and higher kidney weight at 28 days after ischemia. Furthermore, ischemic kidneys from AIF-1 KO when compared to WT mice, showed a significantly higher number of reparative macrophages (CD206/Mrc-1+) which also expressed higher levels of Arginase-1, Ym-1 and CD163. Additionally, BMDMs from AIF-1 KO mice show lowered inflammatory cytokine production (i.e. IL1β, ΙL12p35) after IFN-γ and LPS stimulation. All of this strongly supports that AIF-1 is central to the inflammatory to reparative macrophage phenotypic switch after ischemia. Lowered inflammatory cytokine production prevents augmentation of initial injury while the enrichment in reparative macrophages improves healing of injured kidney tissue, likely through phagocytic clearance, tubular regeneration and angiogenesis.

*Conclusions: Deficiency of AIF-1 enriches the ischemic kidney for reparative macrophages and thereby reducing fibrosis and preserving function. This offers a unique opportunity to modulate the phenotype of kidney macrophages in ischemia and skew them towards a reparative phenotype that can ameliorate the damage caused by ischemia. In the case of kidney transplantation, this provides an avenue to mitigate delayed graft function and increase the utility of organs with greater ischemic insults.

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