Macrophages play a role in acute renal failure by releasing proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, IL-1, IL-6 which are downstream of the TLR (Toll-like receptor) 4 pathway. However, the protective role for macrophages after acute renal failure is less clear. In the colon and lung, macrophages have been shown to be a necessary component of the repair process. Paradoxically, their role in repair are also regulated by TLR4. The overall goal of this project is to determine how the interaction between the ligands for TLR4 and their receptor on macrophage cell surfaces results in the extension and resolution of acute kidney injury. The long term goal is to discern whether modulating the immune system's response to injury would ameliorate acute kidney injury. We hypothesize that injurious macrophages arrive early in ischemia reperfusion injury, while repair macrophages arrive later.
In specific aim 1, flow cytometry will be used as a tool to discriminate various macrophages during the initiation and repair phase during acute kidney injury.
In specific aim 1, we will also determine whether TLR4 regulates the presence of injurious/reparative macrophages in the kidney. Others have shown that there are differences in the concentration of TLR4 ligands at various time points of injury. These different ligands may lead to different downstream signals by TLR4.
In specific aim 2, different ligands will be used to differentiate bone marrow derived macrophages into a reparative or injurious phenotype. Lastly, we will test in specific aim 3 whether adoptive transfer of macrophages may alter the course of acute kidney injury. Despite modern treatment, there has been very little improvement in treating acute kidney injury (AKI). This proposal will investigate how the immune system mediates the kidney's initial response to AKI and its subsequent repair.
| Winterberg, Pamela D; Wang, Yanxia; Lin, Keng-Mean et al. (2013) Reactive oxygen species and IRF1 stimulate IFN? production by proximal tubules during ischemic AKI. Am J Physiol Renal Physiol 305:F164-72 |
| Lu, Christopher Y; Winterberg, Pamela D; Chen, Jianlin et al. (2012) Acute kidney injury: a conspiracy of Toll-like receptor 4 on endothelia, leukocytes, and tubules. Pediatr Nephrol 27:1847-54 |
| Chen, Jianlin; Hartono, John R; John, Reji et al. (2011) Early interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4. Kidney Int 80:504-15 |
| Wu, Qing Qing; Wang, Yanxia; Senitko, Martin et al. (2011) Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPAR?, and HO-1. Am J Physiol Renal Physiol 300:F1180-92 |
| Chen, Jianlin; John, Reji; Richardson, James A et al. (2011) Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury. Kidney Int 79:288-99 |
