2-IPMA Ameliorates PM2.5-Induced Inflammation by Promoting Primary Ciliogenesis in RPE Cells

Abstract

Primary cilia mediate the interactions between cells and external stresses. Thus, dysregulation of primary cilia is implicated in various ciliopathies, e.g., degeneration of the retina caused by dysregulation of the photoreceptor primary cilium. Particulate matter (PM) can cause epithelium injury and endothelial dysfunction by increasing oxidative stress and inflammatory responses. Previously, we showed that PM disrupts the formation of primary cilia in retinal pigment epithelium (RPE) cells. In the present study, we identified 2-isopropylmalic acid (2-IPMA) as a novel inducer of primary ciliogenesis from a metabolite library screening. Both ciliated cells and primary cilium length were increased in 2-IPMA-treated RPE cells. Notably, 2-IPMA strongly promoted primary ciliogenesis and restored PM2.5-induced dysgenesis of primary cilia in RPE cells. Both excessive reactive oxygen species (ROS) generation and activation of a stress kinase, JNK, by PM2.5 were reduced by 2-IPMA. Moreover, 2-IPMA inhibited proinflammatory cytokine production, i.e., IL-6 and TNF-α, induced by PM2.5 in RPE cells. Taken together, our data suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in RPE cells.

Carnitine Protects against MPP+-Induced Neurotoxicity and Inflammation by Promoting Primary Ciliogenesis in SH-SY5Y Cells

“…In order to identify novel metabolites that induce primary ciliogenesis, we previously developed a cell-based screening system using RPE cells. By using this screening system, we have identified several candidates for regulating ciliogenesis by screening a library of fecal metabolites [ 15 ]. Among these candidates, we have identified both L-carnitine and acetyl-L-carnitine as inducers of primary ciliogenesis.…”

“…In this study, we used human telomerase-immortalized RPE cells and RPE/Smo-GFP cells that stably expressed Smo-GFP proteins, as previously described [ 15 ]. The SH-SY5Y neuroblastoma cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA).…”

“…Recently, we have developed a cell-based screening system using retinal pigment epithelium (RPE) cells and have screened a fecal metabolite library in order to identify several putative candidates for regulating primary ciliogenesis, including L-carnitine and acetyl-L-carnitine [ 15 ]. However, the role of carnitine in primary ciliogenesis has remained unclear.…”

Primary Ciliogenesis by 2-Isopropylmalic Acid Prevents PM2.5-Induced Inflammatory Response and MMP-1 Activation in Human Dermal Fibroblasts and a 3-D-Skin Model

“…Recently, we showed that 2-IPMA reduces oxidative stress by inhibition of excessive ROS generation by PM2.5 [22]. In addition, it was reported that 3-IPMA has free radical scavenging activity [16].…”

“…From a cell-based high content screening with a metabolite library, we identified 2-IPMA as a strong inducer for primary ciliogenesis [22]. 2-IPMA is an intermediate metabolite in leucine biosynthesis, synthesized from α-ketoisovalerate and acetyl-coenzyme A, a reaction catalyzed by 2-isopropylmalate synthase in mitochondria and exported into the cytosol [23].…”