Sterols in asthma

Abstract

While sterols regulate immune processes key to the pathogenesis of asthma, inhibition of sterols with statin drugs has shown conflicting results in human asthma. Here, a novel understanding of the impact of sterols on type 17 immune responses and asthma lead us to hypothesize that sterols and statins may be relevant to severe asthma endotypes with neutrophil infiltration.

Keywords: Th17; asthma; neutrophilic; severe; statin; sterol.

Figure 1.

Human severe asthma immune phenotypes [2,3,8]. The innate immune infiltrate in the sputum or bronchoalveolar lavage defines several phenotypes. Type 2^hi asthma is characterized by high eosinophilic infiltration. Type 17/neutrophilic asthma, which is insensitive to steroids, is associated with IL-17 and/or IFN-γ. Mixed eosinophilic/neutrophilic infiltration or, alternatively, lack of granulocytic infiltration, are also observed in severe asthma.

Figure 2.. Regulation of sterol content in the cell [–35].

Immune cells can increase sterol content via uptake from circulating lipoproteins and reduce it by activating ABCA1 and ABCG1 membrane channels that allow cholesterol removal from the cell. Another option to increase cholesterol content is to increase intracellular biosynthesis, a process that occurs downstream of activation of the transcription factors SREBP1/2. Biosynthesis is also negatively regulated through activation of the LXR transcription factors via oxysterols or other signals. Sterol content allows immune cells to regulate a number of crucial processes.

Figure 3.. Sterols and oxysterols can drive murine IL-17 responses [–31].

Sterols and their oxysterol derivatives activate the nuclear receptor ROR-γt, thereby driving a Th17 transcriptional program with IL-17 production. Sterol increases may be promoted by increased sterols of external or biosynthetic origin. Increased sterol biosynthesis is promoted by Protein Arginine Methyltransferase (PRMT)5, which symmetrically demethylates and stabilizes SREBP transcription factors that drive cholesterol biosynthesis. Oxysterols derive from sterols via enzymatic and oxidative processes such as those induced by ozone exposure.TcR: T cell receptor; SREBP: Sterol regulatory element binding protein; Me2: symmetric arginine dimethylation; Chol. Bios. Enz.: cholesterol biosynthetic enzymes.