Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation
Authors: Aiello Sistiana , Podestà Manuel Alfredo , Rodriguez-Ordonez Pamela Y. , Pezzuto Francesca , Azzollini Nadia , Solini Samantha , Carrara Camillo , Todeschini Marta , Casiraghi Federica , Noris Marina , Remuzzi Giuseppe , Benigni Ariela 
Published: January 2020

Significance Statement
Renal macrophages are key cells in controlling processes related to inflammation or repair after ischemia-reperfusion injury. Although macrophages from a donor kidney could also guide adaptive immune responses against renal tissue by virtue of their ability to act as antigen-presenting cells, data are lacking on whether donor-derived renal macrophages can function in this manner after being subjected to transplant-induced ischemia-reperfusion injury. The authors demonstrate in mice that such injury is sufficient to dampen donor renal macrophages’ ability to present antigens, skewing them toward a proreparative phenotype. Donor renal macrophages lacking IL-1R8 failed to orchestrate tissue repair, indicating that IL-1R8 is a key regulator of this shift. IL-1R8 thus represents a pathway that merits exploration in terms of modulating responses against autoantigens and alloantigens after kidney transplant.

Background
In donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells.

Methods
We evaluated the phenotype and function of intragraft CD11c+F4/80+ renal macrophages after cold ischemia. We also assessed the modifications of donor renal macrophages after reversible ischemia-reperfusion injury in a mouse model of congeneic renal transplantation. To investigate the role played by IL-1R8, we conducted in vitro and in vivo studies comparing cells and grafts from wild-type and IL-R8–deficient donors.

Results
Cold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M2 phenotype, and increased surface expression of IL-1R8, diminishing activation mediated by toll-like receptor 4. Ischemic IL-1R8–deficient donor renal macrophages acquired an M1 phenotype, effectively induced IFNγ and IL-17 responses, and failed to orchestrate tissue repair, resulting in severe graft fibrosis and aberrant humoral immune responses.

Conclusions
IL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.