Abstract 5670: KLF5 Controls Macrophage Polarity in Chronic Inflammatory Diseases via S100 Proteins

Abstract

Chronic kidney disease is a major risk factor for atherosclerotic cardiovascular disease. Chronic inflammation has been shown to be involved in both diseases. Therefore, the molecular mechanisms underlying them are likely to be closely linked with each other. We have previously demonstrated that the transcription factor KLF5 is involved in cardiovascular remodeling. In the present study we addressed if KLF5 also plays a role in chronic kidney disease. KLF5 expression levels were increased in various kidney disease models including unilateral ureteral obstruction (UUO) and KLF5 +/− mice ameliorated renal pathology induced by UUO. Genome-wide analyses of potential KLF5 target genes using ChIP-seq and microarrays identified S100A8 and S100A9. S100A8 and A9 are secretory proteins and form a heterodimer. S100A8/A9 induced macrophage accumulation in Matrigel plugs and direct injection of S100A8/A9 into kidneys resulted in infiltration of M1 classically activated macrophages. In KLF5 +/− mice S100A8/A9 expression was reduced and M1 macrophage infiltration was markedly suppressed in UUO. Interestingly, UUO induced infiltration of M2 alternatively activated macrophages during later stages of disease development. In KLF5 +/− mice macrophage activation was shifted to the M2 polarity. M2 macrophages produced anti-inflammatory and pro-fibrotic cytokines, including IL-10 and TGFb1. This shift in macrophage polarity is likely to be primarily accountable for the UUO phenotype of KLF5 +/− , in which tissue inflammation, apoptosis and destruction were ameliorated during early stages, while fibrosis was increased in later time points. Taken together, KLF5 appears to regulate tissue remodeling by controlling the macrophage polarity via inflammatory mediators including S100A8/A9. Because KLF5 is also essential for cardiovascular remodeling, the KLF5-S100 axis may play an important role in chronic inflammation in various chronic diseases, including cardiovascular, renal and metabolic diseases.