The Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts

Abstract

Members of the TLR/IL-1R superfamily mediate ischemia/reperfusion injury and initiate immune response in transplanted organs. In this study, we tested the hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed in the kidney, modulates immune cell activation underlying kidney rejection. In a mouse model of fully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraft Tir8 expression was enhanced compared with naive kidneys. Targeted deletion of Tir8 in the graft exerted a powerful antitolerogenic action leading to acute rejection. Similarly, in a mouse model of kidney graft acceptance induced by costimulation blockade, most Tir8−/− grafts were acutely rejected. Despite similar levels of TLR4, IL-1R, and their ligands, the posttransplant ischemia/reperfusion-induced inflammatory response was more severe in Tir8−/− than in Tir8+/+ grafts and was followed by expansion and maturation of resident dendritic cell precursors. In vitro, Tir8−/− dendritic cell precursors acquired higher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand and TNF-α than Tir8+/+ cells, which may explain the increased frequency of antidonor-reactive T cells and the block of regulatory T cell formation in recipients of a Tir8−/− kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in the kidney. Tir8 expression and/or signaling in donor tissue are envisaged as a novel target for control of innate immunity and amelioration of graft survival.

Ischemia Reperfusion Induces IFN Regulatory Factor 4 in Renal Dendritic Cells, which Suppresses Postischemic Inflammation and Prevents Acute Renal Failure

“…Obviously, controling the activation of resident APCs is sufficient to prevent overshooting postischemic renal inflammation. This concept is supported by the role of SIGIRR in IRI, a constitutively expressed molecule that also specifically inhibits the activation of resident DCs in the postischemic kidney (22,23).…”

“…For example, single Ig/IL-1-related receptor (SIGIRR) is a member of the transmembrane TLR/IL-1R family that inibits TLR2/MyD88 and TLR4/MyD88 signaling via its intracellular domain (18)(19)(20). The constitutive expression of SIGIRR in intrarenal DCs (21) suppresses renal DC activation during IR and thereby limits postischemic sterile inflammation and protects from acute renal failure (22,23). We speculated that beyond such constitutively expressed inhibitors the control of IRIs may also involve inducible inhibitors of TLR signaling in renal DCs.…”

The Toll Interleukin-1 Receptor (IL-1R) 8/Single Ig Domain IL-1R-Related Molecule Modulates the Renal Response to Bacterial Infection

“…The subsequent upregulation of TIR8 later during the infection could, in its turn, avoid the induction of collateral damage due to an exaggerated or prolonged inflammatory response. This corresponds with studies demonstrating that TIR8 deficiency renders mice more susceptible to acute renal isch-emic injury (20), acute graft rejection, and tubular necrosis after kidney allotransplantation (23), while mice with TLR4 and TLR2 deficiencies are less susceptible to acute renal ischemic injury (22,27,32,40). The high level of constitutive TIR8 expression in the kidney during homeostasis could be a mechanism by which organisms try to avoid the induction of a disproportional and detrimental inflammatory response when only few pathogens are present.…”

Toll-Like Receptors and Danger Signaling in Kidney Injury

“…29 -31 Vice versa, mice that lack the TLR signaling inhibitor SIGIRR develop aggravated immunopathology in these models. [32][33][34] Obviously, innate danger control is tightly regulated and genetic variants in TLR signaling modulate risk for renal progression. Now we need to determine in a similar manner whether human gene variants modify tissue pathology in these and other kidney diseases.…”