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

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.