Myeloid derived suppressor cells (MDSC) are a CD11b(+)Gr1(+)population in mice that can be separated into granulocytic (g-MDSC) and monocytic (m-MDSC) subtypes based on their expression of Ly6G and Ly6C.
Both MDSC subtypes are potent suppressors of T cell immunity and their contribution has been investigated in a plethora of diseases including renal cancer, renal transplant, and chronic kidney disease. Whether MDSCs contribute to the pathogenesis of acute kidney injury (AKI) remains unknown. Herein, using human CRP transgenic (CRPtg) and CRP deficient mice (CRP(-/-)) subjected to bilateral renal ischemia-reperfusion injury (IRI), we confirm our earlier finding that CRP exacerbates renal IRI and we show for the first time that this effect is accompanied in CRPtg by a shift in the balance of kidney infiltrating MDSCs towards a suppressive Ly6G(+)Ly6C(low)g-MDSC subtype. In CRPtg, direct depletion of g-MDSCs (using an anti-Gr1 monoclonal antibody) reduced the albuminuria caused by renal IRI, confirming they play a deleterious role. Remarkably, treatment of CRPtg with an antisense oligonucleotide that specifically blocks the human CRP acute phase response also led to a reduction in renal g-MDSC numbers and improved albuminuria after renal IRI. Our study in CRPtg provides new evidence that MDSCs participate in the pathogenesis of renal IRI and shows that their pharmacological depletion is beneficial. If ongoing investigations confirm that CRP is an endogenous regulator of MDSCs in CRPtg, and if this action is recapitulated in humans, then targeting CRP or/and MDSCs might offer a new approach for the treatment of AKI.
American journal of physiology. Renal physiology. 2016 Apr 06 [Epub ahead of print]
Melissa Ann Pegues, Ian L McWilliams, Alexander J Szalai
The University of Alabama at Birmingham., The University of Alabama at Birmingham., University of Alabama at Birmingham