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

Chetna Soni, Stephanie L. Schell, Melinda J. Fasnacht, Sathi Babu Chodisetti, Ziaur S.M. Rahman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)298-315
Number of pages18
JournalImmunology and Cell Biology
Volume96
Issue number3
DOIs
StatePublished - Mar 2018

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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