Phospholipid scramblase-1 regulates innate type 2 inflammation in mouse lungs via CRTH2-dependent mechanisms
Ashley Hernandez-Gutierrez, Sonoor Majid, Adam Eberle, Ashley Choi, Parand Sorkhdini, Dongqin Yang, Alina Xiaoyu Yang, Carmelissa Norbrun, Chuan Hua He, Chang-min Lee, Chun Geun Lee, Jack A. Elias, Yang Zhou
Ashley Hernandez-Gutierrez, Sonoor Majid, Adam Eberle, Ashley Choi, Parand Sorkhdini, Dongqin Yang, Alina Xiaoyu Yang, Carmelissa Norbrun, Chuan Hua He, Chang-min Lee, Chun Geun Lee, Jack A. Elias, Yang Zhou
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Research Article Immunology

Phospholipid scramblase-1 regulates innate type 2 inflammation in mouse lungs via CRTH2-dependent mechanisms

Abstract

Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and nonspecific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that (a) PLSCR1 bound to and physically interacted with chemoattractant receptor-homologous molecule(CRTH2), which is a G-protein-coupled receptor that is expressed on TH2 cells and on multiple immune cells and is commonly used to identify ILC2 cells, and (b) the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2-dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.

Authors

Ashley Hernandez-Gutierrez, Sonoor Majid, Adam Eberle, Ashley Choi, Parand Sorkhdini, Dongqin Yang, Alina Xiaoyu Yang, Carmelissa Norbrun, Chuan Hua He, Chang-min Lee, Chun Geun Lee, Jack A. Elias, Yang Zhou

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Figure 1

The expression of Plscr1 is inhibited by IL-13 and Type 2 inflammation.

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The expression of Plscr1 is inhibited by IL-13 and Type 2 inflammation. ...
(A) WT mice were subjected to HDM administration, lung Plscr1 mRNA expression was assessed by quantitative real-time PCR. Values are mean± SEM with 7–9 mice in each group. Data was assessed with unpaired Student’s t-test. **P ≤ 0.01. (B) Lungs from WT mice with or without HDM challenges were sectioned, SPC, CX3CR1, or Gata-3 was labeled with red fluorescence (Alexa Fluor 594) and Plscr1 was labeled with green fluorescence (Alexa Fluor 488). Nuclei are stained with DAPI (blue). Images are representative of 3 mice. (C) Whole lung lysates from WT (IL-13 Tg (–)) and IL-13 Tg (+) mice were isolated and Plscr1 protein level was then evaluated by Western immunoblot analysis as noted. (D) BAL inflammatory cells were isolated from WT mice. Cells were treated with 30 ng/mL IL-13, and Plscr1 protein level was evaluated using Western immunoblot analysis as noted.