Role of isoLGs and neutrophils in psoriasis-induced renal dysfunction and hypertension

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

Project Summary Psoriasis is a prevalent autoimmune disease involving formation of scaly and pruritic plaques on the skin. Although these skin lesions cause significant negative physical and psychosocial effects, the major morbidity and mortality from psoriasis occurs through markedly increased risk of kidney and cardiovascular disease such as hypertension. Hypertension causes end-organ damage such as kidney disease, which worsens blood pressure elevations in a vicious cycle. A major knowledge gap is in understanding the mechanisms linking cutaneous disease in psoriasis with the increased risk of hypertension and kidney disease. Prior studies have demonstrated a key role for isolevuglandins (IsoLGs), which are products of arachidonic acid oxidation, in the pathogenesis of hypertension. IsoLG formation in dendritic cells is induced at least in part by increased sodium entry via epithelial sodium channels (ENaC). This leads to increased dendritic cell cytokine release to promote T cell IL-17A production. It is unknown whether IsoLGs are formed in psoriasis, however we have exciting preliminary evidence for increased IsoLG formation in cutaneous dendritic cells of a mouse model of psoriasis (KC-Tie2 mice). These mice also exhibit increased renal damage and blood pressure elevations, mirroring the human disease. KC-Tie2 mice also exhibit 10-fold increased renal neutrophil infiltration as well as increased granulopoiesis and circulating levels of the key mediator of granulopoiesis, granulocyte colony stimulating factor (G-CSF). Taken together, these findings have led to the overall hypothesis that cutaneous dendritic cell IsoLG formation in psoriasis promotes T cell IL-17A production which enhances granulopoiesis leading to neutrophil-mediated renal damage and blood pressure elevations. We will test this hypothesis by determining the effect of IsoLG scavenging and ENaC inhibition on renal neutrophil infiltration, renal damage, and blood pressure elevations in KC-Tie2 mice. We will also test whether blocking G-CSF-mediated granulopoiesis and depleting neutrophils alters these endpoints, and whether renal damage and blood pressure elevations in KC- Tie2 mice are mediated through neutrophil extracellular trap formation (NETosis). Finally, we will determine whether these mechanisms are relevant to the human disease by testing the hypothesis that humans with psoriasis and hypertension have increased IsoLGs in circulating monocytes and increased G-CSF and NET formation. Taken together, these studies will use rigorous and innovative approaches to test the novel hypothesis that psoriasis promotes hypertension and kidney disease through IsoLG-mediated mechanisms involving enhanced neutrophil production and activation. This represents a new pathogenic paradigm for psoriasis and associated comorbidities that may lead to new therapies for both psoriasis and associated extracutaneous manifestations such as hypertension and kidney disease. 1