Bone marrow-derived macrophages from a murine model of Sjögren's syndrome demonstrate an aberrant, inflammatory response to apoptotic cells

Abstract

Sjögren's syndrome (SjS) is a female-dominated autoimmune disease involving lymphocytic infiltration of the exocrine glands. We have previously demonstrated cleavage of the TAM (Tyro3, Axl, Mer) receptor Mer is enhanced in SjS, leading to defective efferocytosis. Mer also plays a role in modulating phagocyte inflammatory response to apoptotic cells. Here we investigated the SjS macrophage response to apoptotic cells (AC). Bone marrow-derived macrophages (BMDMs) from SjS-susceptible (SjSs) C57BL/6.NOD-Aec1Aec2 mice and C57BL/6 (B6) controls were treated with either AC or CpG-oligodeoxynucleotides. RNA was collected from macrophages and bulk sequencing was performed to analyze transcripts. Cytokine expression was confirmed by Bio-plex. RT-qPCR was used to determine toll-like receptor (TLR) 7 and 9 involvement in BMDM inflammatory response to apoptotic cells. SjSS BMDMs exhibited a distinct transcriptional profile involving upregulation of a broad array of inflammatory genes that were not elevated in B6 BMDMs by AC. Inhibition of TLR 7 and 9 was found to limit the inflammatory response of SjSS BMDMs to ACs. ACs elicit an inflammatory reaction in SjSS BMDMs distinct from that observed in B6 BMDMs. This discovery of aberrant macrophage behavior in SjS in conjunction with previously described efferocytosis defects suggests an expanded role for macrophages in SjS, where uncleared dead cells stimulate an inflammatory response through macrophage TLRs recruiting lymphocytes, participating in co-stimulation and establishing an environment conducive to autoimmunity.