Increased renal dysfunction and neutrophil infiltration in a mouse model of psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease affecting 2-5% of the global population. As an autoimmune disease, psoriasis is characterized by T cell-mediated hyperproliferation of epidermal keratinocytes. Interestingly, most of the morbidity and mortality from psoriasis is related to increased risk of cardiovascular and renal disease. For example, moderate to severe psoriasis is associated with an approximately 1.5-fold increased risk of chronic kidney disease. Neutrophils are increased in the skin and circulation of patients with psoriasis, and markers of neutrophil activation are associated with extra-cutaneous manifestations of psoriasis including vascular inflammation. However, the molecular mechanisms linking psoriasis and kidney disease remain unclear. We hypothesized that increased neutrophil infiltration of the kidney through enhanced granulopoiesis promotes renal dysfunction in psoriasis. Using a KC-Tie2 mouse model of psoriasis with keratinocyte-specific overexpression of the angiopoietin receptor Tie2, we found that KC-Tie2 mice compared to littermate controls exhibit significantly increased urine albumin, suggestive of renal dysfunction. KC-Tie2 mice also exhibit significantly increased kidney/body weight and heart/body weight ratios compared to littermate controls. To determine a mechanism for the increased renal dysfunction in these mice, we assessed skin and renal immune cell content using flow cytometry. KC-Tie2 mice had increased neutrophils in the skin, as well as an approximately 10-fold increase in neutrophils in the kidneys. This increase in renal neutrophils in KC-Tie2 mice was relatively selective as there were no differences in the number of renal dendritic cells, lymphocytes, or monocytes and a modest but significant increase in macrophages. We also observed a selective increase in neutrophils in the spleen of KC-Tie2 mice. Given these findings and prior reports of increased circulating neutrophils in KC-Tie2 mice, we assessed mediators of granulopoiesis in the serum and found a significant increase in granulocyte colony stimulating factor (GCSF) in KC-Tie2 mice. Taken together, these results provide evidence for increased renal dysfunction in a mouse model of psoriasis coincident with marked increases in renal neutrophils that may represent a novel mechanism linking skin inflammation to renal dysfunction through enhanced granulopoiesis. MRA is funded by NIH K08HL153786-01. JM is funded by 2T32GM007569. NW is funded by NIH R01 AR075777, NIH R01 AR073196, NIH P50 CORT AR070590, and National Psoriasis Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.