Crucial role of Mer tyrosine kinase in the maintenance of SIGN-R1 + marginal zone macrophages.

Autor: Soni C; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA., Schell SL; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA., Fasnacht MJ; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA., Chodisetti SB; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA., Rahman ZS; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Jazyk: angličtina
Zdroj: Immunology and cell biology [Immunol Cell Biol] 2018 Mar; Vol. 96 (3), pp. 298-315. Date of Electronic Publication: 2018 Jan 18.
DOI: 10.1111/imcb.12003
Abstrakt: Mer Tyrosine Kinase receptor (Mer) is involved in anti-inflammatory efferocytosis. Here we report elevated spontaneous germinal center (Spt-GC) responses in Mer-deficient mice (Mer -/- ) that are associated with the loss of SIGN-R1 + marginal zone macrophages (MZMs). The dissipation of MZMs in Mer -/- mice occurs independently of reduced cellularity or delocalization of marginal zone B cells, sinusoidal cells or of CD169 + metallophillic macrophages. We find that MZM dissipation in Mer -/- mice contributes to apoptotic cell (AC) accumulation in Spt-GCs and dysregulation of the GC checkpoint, allowing an expansion of DNA-reactive B cells in GCs. We further observe that bone marrow derived macrophages from Mer -/- mice produce more TNFα, and are susceptible to cell death upon exposure to ACs compared to WT macrophages. Anti-TNFα Ab treatment of Mer -/- mice is, however, unable to reverse MZM loss, but results in reduced Spt-GC responses, indicating that TNFα promotes Spt-GC responses in Mer -/- mice. Contrary to an anti-TNFα Ab treatment, treatment of Mer -/- mice with a synthetic agonist for the transcription factor LXRα rescues a significant number of MZMs in vivo. Our data suggest that Mer-LXRα signaling plays an important role in the differentiation and maintenance of MZMs, which in turn regulate Spt-GC responses and tolerance.
(© 2018 The Authors Immunology and Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.)
Databáze: MEDLINE
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