Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

Abstract

Ischemia-reperfusion injury during kidney transplantation predisposes to delayed graft function, rejection, and premature graft failure. Exacerbation of tissue damage and alloimmune responses may be explained by necroinflammation: an autoamplification loop of cell death and inflammation, which is mediated by the release of damage-associated molecular patterns (eg, high-mobility group box-1; HMGB1) from necrotic cells that activate both innate and adaptive immune pathways. Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is upregulated on injured proximal tubular epithelial cells and enables them to clear apoptotic and necrotic cells. Here we show a pivotal role for clearance of dying cells in regulating necroinflammation in a syngeneic murine kidney transplant model. We found persistent KIM-1 expression in KIM-1 kidney grafts posttransplantation. Compared to recipients of KIM-1 kidneys, recipients of KIM-1 kidneys exhibited significantly more renal dysfunction, apoptosis and necrosis, tubular obstruction, and graft failure. KIM-1 grafts also had more inflammatory cytokines, infiltrating neutrophils, and macrophages compared to KIM-1 grafts. Most significantly, passive release of HMGB1 from apoptotic and necrotic cells led to dramatically higher serum HMGB1 levels and increased proinflammatory macrophages in recipients of KIM-1 grafts. Our data identify an endogenous protective mechanism against necroinflammation in kidney grafts that may be of therapeutic relevance in transplantation.

Recombinant apoptosis inhibitor of macrophage protein reduces delayed graft function in a murine model of kidney transplantation

“…In a subsequent study, when we exposed donor kidneys from KIM-1 deficient mice to both warm and cold ischemia and then transplanted them into wild-type mice. In the same study, we observed greater renal and systemic inflammation as well as increased susceptibility to renal dysfunction and tissue damage, compared to transplanted kidneys from wild-type donors [18]. Taken together, these studies suggest that KIM-1 plays a protective role in mitigating tissue damage by inhibiting necroinflammation [18].…”

“…We chose this time point based on the literature and sustained viability of recipient mice [26]. The primary outcome was renal function at 2 days and was quantified by serum creatinine as previously described [18]. We chose this timepoint as peak graft injury and mortality occurs within the first 3 days of surgery if the graft fails [26].…”

“…The number of animals used were 4-6/ group for each experiment as per the figure legends. These numbers were based on a previous study [18].…”

Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion

“…In addition, necroinflammation has been found to be involved in primary and distant organ injury following acute kidney injury [58, 59]. However, the role of necroinflammation in intestinal I/R, especially links with ferroptosis, remains unexplored.…”

Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1

“…Further studies may need to be conducted to elucidate intrinsic mechanisms of the IIR ALI. Firstly, necroinflammation has been found to be involved in distant organ injury [ 26 , 27 ]. The activated innate immune system has been reported to initiate local inflammation and subsequently lead to necroinflammation in remote organs via spreading damage-associated molecular patterns and cytokines to the systemic circulation from primary ischemic organs [ 27 , 28 ].…”