Targeting macrophages during kidney repair and regeneration: Regulation of inflammatory and reparative macrophage activation by crosstalk between innate immune and WNT/beta-catenin pathways in acute kidney injury

• Applicant: Dr. Julia Lichtnekert
• Subject Area: Nephrology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 230480870

The cellular mechanisms that regulate macrophages in repair and regeneration in kidney inflammation are unresolved at present. Besides their well known function to mediate acute and chronic inflammation in the kidney, there is accumulating evidence for their regenerative and reparative role during acute kidney injury. Macrophage plasticity and functional polarization result in different phenotypes depending on distinct signals. However the precursor cells, either circulating monocytes or resident macrophages, are similar regardless of the later function. What are the mechanisms governing the differentiation of these precursors into macrophages that stimulate repair in the kidney? Release of IL-10 defines reparative macrophages. There is evidence that the WNT/beta-catenin signaling pathway is active in macrophages resulting in a high IL-10 production. In the proposed research project the regulation of macrophages in repair and regeneration in sterile kidney inflammation using a mouse model of AKI will be investigated. The central hypothesis is that co-activation of the WNT/beta-catenin pathway and the innate immune system stimulates a regenerative macrophage phenotype in AKI. Therefore in this project the following objectives will be conducted: 1st, IL-10 positive or WNT/beta-catenin signaling positive macrophages will be characterized during kidney repair after ischemic injury. 2nd, the signaling pathway in reparative macrophages will be then dissected by genetic studies and using small molecular modulators in vitro. 3rd, the functional consequences of modulation of the WNT signaling pathway will be determined during kidney repair by genetic and small molecular modulation in vivo. These studies will account for identifying a new cellular mechanism for kidney repair and regeneration and provide a new therapeutic approach for inflammatory kidney diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professor Jeremy Stuart Duffield, Ph.D.; Professor Dr. Stuart J. Shankland