IRF-1 Promotes Inflammation Early after Ischemic Acute Kidney Injury

Abstract

Acute renal ischemia elicits an inflammatory response that may exacerbate acute kidney injury, but the regulation of the initial signals that recruit leukocytes is not well understood. Here, we found that IFN regulatory factor 1 (IRF-1) was a critical, early proinflammatory signal released during ischemic injury in vitro and in vivo. Within 15 min of reperfusion, proximal tubular cells of the S3 segment produced IRF-1, which is a transcription factor that activates proinflammatory genes. Transgenic knockout of IRF-1 ameliorated the impairment of renal function, morphologic injury, and inflammation after acute ischemia. Bone marrow chimera experiments determined that maximal ischemic injury required IRF-1 expression by both leukocytes and radioresistant renal cells, the latter identified as S3 proximal tubule cells in the outer medulla by in situ hybridization and immunohistochemistry. In vitro, reactive oxygen species, generated during ischemia/reperfusion injury, stimulated expression of IRF-1 in an S3 proximal tubular cell line. Taken together, these data suggest that IRF-1 gene activation by reactive oxygen species is an early signal that promotes inflammation after ischemic renal injury.

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI

“…3) We previously reported increased expression of IRF1 by renal tubule cells exposed to ROS in vitro (56). We now confirm and extend this result by showing ROS also stimulated expression of IFN␣s (Fig.…”

“…We previously showed that ROS generated during ischemia (34,35,58) increases the expression of IRF1 in proximal tubule cells in vitro (56). We now find that IFN␣ mRNA is significantly increased in tubule cells following exposure to ROS in vitro, and this increase is prevented by IRF1 knockdown (Fig.…”

“…To understand how IFN␣ is regulated in renal tubules, we chose to study IRF1. This choice was based on three previous observations: 1) overexpression of this transcription factor increases IFN␣ but not IFN␤ gene expression in vitro (3, 4, 10, 48, 57); 2) we previously showed that genetic knockout of IRF1 ameliorated injury (56) and concluded that IRF1 has an important maladaptive role during ischemic AKI; and 3) we found that IRF1 is expressed in vivo very early following ischemia (within 15 min) and therefore is a prime candidate to regulate early maladaptive genes (56).…”

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

“…IRF4 was found to be induced not before 24 h after ROS exposure in spleen monocytes, which was consistent with increased renal IRF4 expression 24 h after renal artery clamping, a phenomenon entirely prevented by antioxidant treatment. As such, oxidative stress does not induce IRF4 as an early response gene like IRF1, which was previously shown to respond within 15 min of oxidative stress (41). The delayed IRF4 response versus the rapid induction of IRF1 is interesting because IRF-1 promotes postischemic renal inflammation and acute renal failure (41), whereas our data documents the opposite for IRF4.…”

“…Our data document that oxidative stress adds onto the list of triggers for IRF4 induction, which suggests IRF4 regulates the activation of resident APCs in ischemic tissues. This was evidenced by exposing monocytes to hypoxanthine and xanthineoxidase, which generate ROS and induce stress response genes like HSP70 in a controlable manner in vitro (41). IRF4 was found to be induced not before 24 h after ROS exposure in spleen monocytes, which was consistent with increased renal IRF4 expression 24 h after renal artery clamping, a phenomenon entirely prevented by antioxidant treatment.…”