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.

Hye-Won Na,Ji Yeon Choi,Ji-Eun Bae,Hyoung-June Kim,Daejin Min,Na Yeon Park,Hyunjung Choi,Doo Sin Jo,Yoon Jae Kim,Dong-Hyung Cho,Eun Sung Kim,Joon Bum Kim,Yong Hwan Kim

doi:10.3390/ijms222010941

Abstract

Particulate matters (PMs) increase oxidative stress and inflammatory response in different tissues. PMs disrupt the formation of primary cilia in various skin cells, including keratinocytes and melanocytes. In this study, we found that 2-isopropylmalic acid (2-IPMA) promoted primary ciliogenesis and restored the PM2.5-induced dysgenesis of primary cilia in dermal fibroblasts. Moreover, 2-IPMA inhibited the generation of excessive reactive oxygen species and the activation of stress kinase in PM2.5-treated dermal fibroblasts. Further, 2-IPMA inhibited the production of pro-inflammatory cytokines, including IL-6 and TNF-α, which were upregulated by PM2.5. However, the inhibition of primary ciliogenesis by IFT88 depletion reversed the downregulated cytokines by 2-IPMA. Moreover, we found that PM2.5 treatment increased the MMP-1 expression in dermal fibroblasts and a human 3-D-skin model. The reduced MMP-1 expression by 2-IPMA was further reversed by IFT88 depletion in PM2.5-treated dermal fibroblasts. These findings suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in dermal fibroblasts.

Highlights

IntroductionNumerous studies have shown that PM2.5 is associated with cardiovascular diseases and pulmonary diseases by causing endothelial dysfunction and epithelium injury [1,2], the patho-physiological effect of PM2.5 on the skin has been limitedly elucidated
Fine particulate matters (PMs, (PM2.5 = diameters < 2.5 μm)) in air pollution are heterogeneous pollutants composed of several molecules
From a cell-based high content screening with a metabolite library, we identified 2IPMA as a strong inducer for primary ciliogenesis [22]. 2-isopropylmalic acid (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]

Summary

Introduction

Numerous studies have shown that PM2.5 is associated with cardiovascular diseases and pulmonary diseases by causing endothelial dysfunction and epithelium injury [1,2], the patho-physiological effect of PM2.5 on the skin has been limitedly elucidated. The interest in PMs on the skin has greatly increased and recent epidemiological studies indicate PM2.5 disrupts skin homeostasis [3]. PMs can penetrate the epidermis in normal intact skin and cause cutaneous diseases, such as atopic dermatitis and psoriasis, by increasing oxidative stress and inflammatory response [4]. Cilia as microtubule-based cellular organelles are maintained by an intraflagellar transport proteins (IFTs) and dysregulation of ciliogenesis is associated with various human diseases, known as ciliopathies [5,6]

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