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

• Published in: International journal of molecular sciences 2021-09, Vol.22 (18), p.9711
• Main Authors: Witas, Richard, Rasmussen, Astrid, Scofield, Robert H, Radfar, Lida, Stone, Donald U, Grundahl, Kiely, Lewis, David, Sivils, Kathy L, Lessard, Christopher J, Farris, A Darise, Nguyen, Cuong Q
• Format: Article
• Language: English
• Subjects: Ablation; ADAM17 Protein - metabolism; Age; Animal models; Animals; Antibodies, Antinuclear - chemistry; Apoptosis; Autoantibodies; Autoantibodies - metabolism; Autoimmune diseases; Autoimmunity; c-Mer Tyrosine Kinase - genetics; Cell activation; Cytokines; Disease; Disease Models, Animal; efferocytosis; Enzyme-linked immunosorbent assay; Enzymes; Exocrine glands; Female; Gene Expression Regulation, Enzymologic; Humans; Immune system; Immunological tolerance; Innate immunity; Kinases; Ligands; Macrophages; Macrophages - metabolism; Male; Mer receptor; Metalloproteinase; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Phenotype; Protein-tyrosine kinase receptors; Rac1 protein; Saliva; Saliva - metabolism; Signal Transduction; Sjogren's syndrome; Sjogren's Syndrome - immunology; Sjogren's Syndrome - metabolism; Sjögren’s syndrome; Submandibular gland; Thymocytes - metabolism; Tumor necrosis factor-TNF; Tyrosine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22189711

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 (SjS ) C57BL/6.NOD- 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 SjS mice, as evidenced by reduced Rac1 activation in SjS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjS 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 SjS mice.