Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a de facto innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli. Isolated monocytes were stimulated with SLE-typical nuclear antigens, neutrophil extracellular traps (NETs), and apoptotic microparticles (MPs) or plasma from SLE patients. After five days of rest, cells were restimulated with Toll-like receptor (TLR) agonists, and cytokine production was measured using ELISA. Functional, transcriptomic and epigenetic changes in monocytes from SLE patients were evaluated by ex vivo stimulations, flow cytometric analysis, RNA sequencing, and chromatin immunoprecipitation (ChIP) sequencing for histone 3 lysine 4 trimethylation. We found that in vitro, both MPs and NETs, as well as plasma from SLE patients, can induce trained immunity. Furthermore, circulating monocytes from SLE patients produce increased levels of pro-inflammatory cytokines after stimulation with TLR ligands, indicating trained immunity. This is accompanied by deregulation in histone 3 lysine 4 trimethylation and increased expression of metabolism and inflammation-related genes. Our findings demonstrate that trained immunity can develop against nuclear antigens and that trained immunity is involved in the immunological dysregulation in SLE patients.