Mer tyrosine kinase (MerTK) deficiency drives the loss of marginal zone macrophages with subsequent accumulation of apoptotic cells and dysregulation of germinal centers

Abstract

Abstract MerTK is a scavenger receptor involved in anti-inflammatory efferocytosis. We previously reported that MerTK deficiency on a mixed B6 and 129 background (B6-129.MerKO) led to dysregulated germinal center (GC) responses and accumulation of apoptotic cells (ACs), primarily in the GCs. Here we report that the dysregulation of GCs in B6-129.MerKO mice strongly correlates with the loss of marginal zone macrophages (MZMs) starting at two months of age. In addition to MerTK, MZMs also express other AC-scavenger receptors like SIGNR1, MARCO and Tim-4, which are also lost from the splenic MZ of B6-129.MerKO mice. We do not observe a loss or translocation of marginal zone B cells (MZBs) or marginal zone metallophillic macrophages (MMMs) from the marginal zone, indicating the exclusive role of MZMs in deregulated GC responses observed in this model. Preliminary results using splenic and bone marrow derived macrophages show reduced expression of a pro-survival heat shock protein Hsp27 and its phosphorylation through p38 and MAPKAPK-2 in the absence of MerTK. We also observe increased cell death in MerTK deficient macrophages vs. WT macrophages, when challenged with ACs. Our data indicate that reduced Hsp27 expression due to MerTK deficiency may lead to cell death of MZMs. We are further investigating if the increased availability of self-antigens through AC accumulation, due to the loss of MZMs can lead to positive selection of self-reactive B cells in the GCs, causing autoimmunity. Our data indicate that MerTK deficiency and ACs enhance antigen presentation by macrophages, DCs and B cells. In accordance, we observe an increase in activated T cells in MerTK deficient mice, which may promote dysregulation of GC responses observed in this model.