Liver X Receptor Expression and Pentraxin 3 Production in Chronic Rhinosinusitis and Sinonasal Mucosal Fibroblast Cells.

Yih-Jeng Tsai,Wen-Bin Wu,Sheng-Dean Luo,Ping-Hung Shen

doi:10.3390/jcm10030452

Abstract

The long pentraxin 3 (PTX3) is a prototypic molecule for recognizing pathogens. Liver X receptors (LXRs), belonging to nuclear receptors (NRs) for cholesterol metabolism through heterodimerizing with other NRs, were recently reported to participate in inflammation. However, their roles in chronic rhinosinusitis without nasal polyps (CRSsNP) are unclear. Therefore, this study was sought to explore roles of LXRs in chronic rhinosinusitis (CRS) sinonasal tissues and derived fibroblasts. Immunohistochemistry indicated that LXRα and β expression and lipid/fat deposition were differentially expressed in the control and CRSsNP nasal mucosa. GW7647 (a peroxisome proliferator activated receptor α (PPARα) agonist) and GW3965 (a dual agonist for LXRα and β) significantly caused PTX3 induction in the fibroblast cells. GW3965 induced PTX3 mRNA and protein expression, and the induction substantially led to PTX3 secretion. Meanwhile, an endogenous agonist-cholesterol had a similar enhancing effect on the induction of PTX3 protein. LXR siRNA knockdown to lower LXRα or β expression significantly compromised PTX3 induction. Interestingly, GW3965 also induced phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) activation and its inhibition reduced PTX3 expression. Collectively, we demonstrated here for the first time that CRSsNP nasal mucosa differentially expresses LXRα and β and deposits lipids/fats that may contain cholesterol metabolites to activate LXRs. Activation of LXRs leads to PTX3 production in sinonasal mucosa-derived fibroblasts. Our previous study showed PTX3 overexpression in the nasal cavity of CRSsNP, whereas this study highlights that cholesterol metabolites and LXR activation regulate PTX3 production and may contribute to antimicrobial activity and tissue repair during CRSsNP progression.

Highlights

PPARs and Liver X receptors (LXRs), and both of them may have a role in inflammation, this study focused on how nuclear receptors (NRs) agonists affect pentraxin 3 (PTX3) production in primary cultured human fibroblasts obtained from chronic rhinosinusitis without nasal polyps (CRSsNP) nasal mucosa, namely human nasal mucosa-derived fibroblasts
To determine the LXR expression patterns, the sinus mucosae and nasal mucosae obtained from patients with control and CRSsNP were collected, respectively, and IHC was performed using antiLXRα or β Ab as a probe
We provide here the first evidence that LXR activation by a selective LXR agonistGW3965 and cholesterol induces long PTX3 expression and release in human nasal mucosa-derived fibroblasts (hNMDFs) through activation of LXRα and β, and involvement of the PI3K/Akt signaling pathway

Summary

Introduction

Nuclear receptors (NRs) such as peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor (LXR) play critical roles in lipid metabolism and inflammation [1]. The endogenous agonists for PPARγ [2] are fatty acids, whereas those for LXR are oxysterols [3]. LXRs were originally discovered as orphan receptors without corresponding ligands but were subsequently identified as NRs for an oxidation metabolite of cholesterol, namely oxysterols. LXRs consist of two different isoforms (isotypes), including LXRα and β. They share large sequence homology but with distinct tissue distributions [4]. LXRα is highly expressed in the small intestine, liver and kidney with a high degree of expression in adipose tissue and macrophages, but only a little in other tissues. LXRβ is expressed in whole body tissue cells [5]

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Discussion

Conclusion