Just parking, a tickle to follow up. Nothing to see here.....
Immunol Cell Biol. 2018 Mar;96(3):298-315. doi: 10.1111/imcb.12003. Epub 2018 Jan 18.
Crucial role of Mer tyrosine kinase in the maintenance of SIGN-R1+ marginal zone macrophages.
Soni C1, Schell SL1, Fasnacht MJ1, Chodisetti SB1, Rahman ZS1.
1
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
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 TNFa, and are susceptible to cell death upon exposure to ACs compared to WT macrophages. Anti-TNFa Ab treatment of Mer-/- mice is, however, unable to reverse MZM loss, but results in reduced Spt-GC responses, indicating that TNFa promotes Spt-GC responses in Mer-/- mice. Contrary to an anti-TNFa Ab treatment, treatment of Mer-/- mice with a synthetic agonist for the transcription factor LXRa rescues a significant number of MZMs in vivo. Our data suggest that Mer-LXRa signaling plays an important role in the differentiation and maintenance of MZMs, which in turn regulate Spt-GC responses and tolerance. |
