Retinol Saturase Knock-Out Mice are Characterized by Impaired Clearance of Apoptotic Cells and Develop Mild Autoimmunity.

Zsolt Sarang,Zsuzsa Szondy,Judit Bedekovics,Gábor Méhes,Gábor Nagy,Lívia Beke,Krzysztof Palczewski,Ralph Rühl,Tibor Sághy,Zsófia Budai,Alexander R Moise,László Ujlaky-Nagy

doi:10.3390/biom9110737

Zsolt Sarang, Zsuzsa Szondy + Show 10 more

Open Access

https://doi.org/10.3390/biom9110737

Copy DOI

Abstract

Apoptosis and the proper clearance of apoptotic cells play a central role in maintaining tissue homeostasis. Previous work in our laboratory has shown that when a high number of cells enters apoptosis in a tissue, the macrophages that engulf them produce retinoids to enhance their own phagocytic capacity by upregulating several phagocytic genes. Our data indicated that these retinoids might be dihydroretinoids, which are products of the retinol saturase (RetSat) pathway. In the present study, the efferocytosis of RetSat-null mice was investigated. We show that among the retinoid-sensitive phagocytic genes, only transglutaminase 2 responded in macrophages and in differentiating monocytes to dihydroretinol. Administration of dihydroretinol did not affect the expression of the tested genes differently between differentiating wild type and RetSat-null monocytes, despite the fact that the expression of RetSat was induced. However, in the absence of RetSat, the expression of numerous differentiation-related genes was altered. Among these, impaired production of MFG-E8, a protein that bridges apoptotic cells to the αvβ3/β5 integrin receptors of macrophages, resulted in impaired efferocytosis, very likely causing the development of mild autoimmunity in aged female mice. Our data indicate that RetSat affects monocyte/macrophage differentiation independently of its capability to produce dihydroretinol at this stage.

Highlights

Timed induction of apoptosis and the proper clearance of apoptotic cells play a crucial role in the maintenance of tissue homeostasis
Since we found that neuropeptide Y (NPY) is hardly expressed by retinol saturase (RetSat)-null macrophages (Table 1) but NPY was reported to promote the M2 phenotypic change of macrophages [35], which is known to be associated with enhanced phagocytic capacity [36], we tested whether lack of NPY
DC-STAMP expression in dendritic cells might contribute to the development of autoimmunity in Cumulatively, our data indicate that RetSat affects the differentiation of macrophages, but it might not be related to its ability to produce dihydroretinol, at least not during the monocyte/macrophage differentiation phase

Summary

Introduction

Timed induction of apoptosis and the proper clearance of apoptotic cells play a crucial role in the maintenance of tissue homeostasis. Dying cells are normally taken up by macrophages by simultaneously using several phagocytic receptors. The appearance of phosphatidylserine (PS) on the surface of the apoptotic cell is the most ubiquitous indicator of apoptosis [2]. It is recognized by BAI1 [3], stabilin-2 [4], and Tim-4 [5] directly, while other phagocytic receptors utilize the bridging molecule milk fat globule EGF-factor 8 (MFG-E8) [6], thrombospondin-1 [7], Gas, Protein S [8], or complement

Methods

Results

Discussion

Conclusion