A new study published in the Journal of the American Society of Nephrology reports that deletion of myeloid interferon regulatory factor 4, or IRF4, may be protective against kidney fibrosis following severe ischemic renal injury by reducing macrophage recruitment and activation.
IRF4 is a transcription factor that mediates polarization of macrophages to the M2 anti-inflammatory phenotype, and plays important roles in oncogenesis and immunity. Researchers have previously associated macrophage polarization and kidney injury. However, the role of IRF4 in recovery of acute kidney injury (AKI) remains unknown.
“We investigated whether specific deletion of myeloid IRF4 altered recovery from ischemic injury to the kidneys, and surprisingly, subsequent development of renal fibrosis was mitigated,” said Raymond Harris, M.D., the Ann and Roscoe R. Robinson Chair in Nephrology at Vanderbilt University Medical Center and senior author on the study. Kensuke Sasaki, Ph.D., a postdoctoral researcher at Vanderbilt, is first author.
AKI Fibrosis Model
Working closely with his longtime collaborator, Ming-Zhi Zhang, M.D., an associate professor of medicine at Vanderbilt, Harris and his team used a mouse model of ischemic kidney injury to study development of progressive fibrosis after severe AKI, which is the ultimate mechanism for kidney failure. Incomplete healing following severe AKI can lead to chronic kidney disease, which still affects approximately 14 percent of Americans.
“We’ve been interested in the role of macrophages in kidney injury for some time,” Harris said. “The entry of macrophages into injured renal tissue causes the release of inflammatory mediators, which exacerbates injury, and if you don’t allow the kidney to recover, persistence of macrophages leads to progressive scarring of the kidney.”
The Protective Role of IRF4
While macrophage proliferation and polarization to the M2 phenotype is involved in AKI recovery, infiltrating macrophages also produce profibrotic factors. Their persistence may contribute to interstitial fibrosis in the kidney, Harris said.
The researchers found that mice with macrophage-specific deletion of the gene encoding IRF4 exhibited reduced renal fibrosis four weeks after severe AKI and fewer activated macrophages. The deletion also protected against renal fibrosis in unilateral ureteral obstruction. Furthermore, bone marrow-derived monocytes from mice without IRF4 had reduced chemotactic responses, and were less sensitive to macrophage signaling. Renal macrophage infiltration in response to AKI was greatly reduced in these genetically modified mice, as well as in wild-type mice with inhibition of AKT activity.
“We were surprised to learn about the role of IRF4 and its function to mediate monocyte recruitment to the injured tissue,” Harris said. “Our results show that macrophages play a key role in exacerbation of kidney injury.”
Harris further explained that IRF4-dependent signaling may be a common mechanism for macrophage recruitment in response to inflammatory stimuli. A better understanding of these mechanisms may prove useful for the rational design of effective therapeutic strategies for a variety of kidney diseases.
“The mechanism we identified could play a role in other kidney diseases, such as diabetic nephropathy, but we haven’t done these studies yet,” Harris said. “We’re excited about the diverse range of nephrology research that is ongoing.”
Currently, Harris and his team are using other models of kidney injury to determine what causes the kidney to develop progressive fibrosis and how it might be prevented.