Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells.

Sun-Hye Shin,Yael Pewzner-Jung,Woo-Jae Park,Hee-Yeon Kim,Joo-Won Park,Kyung-Ah Cho,Anthony H Futerman,So-Yeon Kim,Hee-Soo Yoon,Sung-Ae Jung

doi:10.3390/ijms22052713

Abstract

(1) Background: six mammalian ceramide synthases (CerS1–6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22–C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

Highlights

We compared the type of immune response elicited by OVA challenge by measuring levels of Th1 IFN-γ, Th2 IL-4, and Th17 IL-17 in bronchoalveolar lavage (BAL) fluid (Figure 1C–E)
We examined the proliferation of CD4+ T cells from wild type (WT) and CerS2 null mice to confirm whether the differential cytokine profiles observed in OVA-challenged mice were due to cell proliferation
Because we confirmed that CerS2-null CD4+ T cells weakly promoted Th2 response, both in vivo and in vitro, we investigated the activation of T cell receptor (TCR) signal proteins, such as extracellular-regulated kinase (ERK) and AKT by performing western blotting

Summary

Introduction

Asthma is a multi-faceted disease characterized by chronic airway inflammation and variable remodeling, which results in a range of clinical presentations, such as wheezing, coughing, shortness of breath, chest tightness, bronchial hyper-responsiveness, and airflow limitation [1]. Asthma can substantially impact the quality of life, and asthma is globally ranked 16th among the leading causes of years lived with disabilities, and 28th among the leading causes of disease burdens, as measured by disability-adjusted life years [2]. Asthma affects approximately 300 million people worldwide, and it is estimated that a further 100 million may be affected by 2025 [2]. Airway inflammation is a prominent feature of asthma, and type 2 immune response-associated inflammation occurs in >80% of children and in the majority of adults with asthma caused by sensitization to environmental allergens [1]

Methods

Results

Discussion

Conclusion