Defective Efferocytosis in a Murine Model of Sjögren's Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor.

Richard Witas,Lida Radfar,Robert H Scofield,A Darise Farris,Kiely Grundahl,Astrid Rasmussen,David Lewis,Cuong Q Nguyen,Donald U Stone,Kathy L Sivils,Christopher J Lessard

doi:10.3390/ijms22189711

Abstract

Sjögren’s syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjSS) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjSS mice, as evidenced by reduced Rac1 activation in SjSS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjSS mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjSS mice.

Highlights

Sjögren’s syndrome (SjS) is an autoimmune disease that primarily affects women and is characterized by dry mouth and dry eye due to lymphocytic infiltration into the salivary and lacrimal glands [1]
Mer is the most essential TAM receptor for macrophage efferocytosis, and defective efferocytosis can result in systemic autoimmune diseases
Considering that one of the primary roles of Mer is to facilitate efferocytosis by macrophages and that delayed efferocytosis is believed to contribute to autoimmunity, we evaluated the numbers of apoptotic cells in Mer knockout (MerKO) submandibular gland (SMG)

Summary

Introduction

Sjögren’s syndrome (SjS) is an autoimmune disease that primarily affects women and is characterized by dry mouth and dry eye due to lymphocytic infiltration into the salivary and lacrimal glands [1]. Previous studies have identified aberrant gland development and accumulation of apoptotic cells in the salivary glands of both SjS patients [5] and mouse models [6]. The aberrant apoptosis in SjS patient tissue has been reported to affect the minor salivary gland’s ductal and acinar epithelial cells [12,13]. Inflammatory cytokines tumor necrosis factor α and interferon γ were determined to induce apoptosis in a human salivary gland cell line, to anti-Ro and anti-La anti-nuclear autoantibodies (ANA) that initiated apoptosis in primary salivary gland epithelial cells [14,15]. Data obtained from the studies of both preclinical SjS models and SjS patient samples indicate a marked propensity for apoptosis of epithelial cells coupled with increased detection of dead cells within the exocrine glands

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