Identification of alterations in macrophage activation associated with disease activity in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is characterized by abnormalities in B cell and T cell function, but the role of disturbances in the activation status of macrophages (Mϕ) has not been well described in human patients. To address this, gene expression profiles from isolated lymphoid and myeloid populations were analyzed to identify differentially expressed (DE) genes between healthy controls and patients with either inactive or active SLE. While hundreds of DE genes were identified in B and T cells of active SLE patients, there were no DE genes found in B or T cells from patients with inactive SLE compared to healthy controls. In contrast, large numbers of DE genes were found in myeloid cells (MC) from both active and inactive SLE patients. Among the DE genes were several known to play roles in Mϕ activation and polarization, including the M1 genes STAT1 and SOCS3 and the M2 genes STAT3, STAT6, and CD163. M1-associated genes were far more frequent in data sets from active versus inactive SLE patients. To characterize the relationship between Mϕ activation and disease activity in greater detail, weighted gene co-expression network analysis (WGCNA) was used to identify modules of genes associated with clinical activity in SLE patients. Among these were disease activity-correlated modules containing activation signatures of predominantly M1-associated genes. No disease activity-correlated modules were enriched in M2-associated genes. Pathway and upstream regulator analysis of DE genes from both active and inactive SLE MC were cross-referenced with high-scoring hits from the drug discovery Library of Integrated Network-based Cellular Signatures (LINCS) to identify new strategies to treat both stages of SLE. A machine learning approach employing MC gene modules and a generalized linear model was able to predict the disease activity status in unrelated gene expression data sets. In summary, altered MC gene expression is characteristic of both active and inactive SLE. However, disease activity is associated with an alteration in the activation of MC, with a bias toward the M1 proinflammatory phenotype. These data suggest that while hyperactivity of B cells and T cells is associated with active SLE, MC potentially direct flare-ups and remission by altering their activation status toward the M1 state.

Analysis of Gene Expression from Systemic Lupus Erythematosus Synovium Reveals a Profile of Activated Immune Cells and Inflammatory Pathways

“…IPA revealed monocyte/macrophagemediated phagocytosis and NO and ROS production signaling pathways, and GSVA confirmed gene expression profiles of both inflammatory M1 and inhibitory M2 macrophages in LA. This aligns with prior histology suggesting the presence of infiltrating macrophages [9] and recent analysis of myeloid cells in SLE blood associated an M1 inflammatory phenotype with active versus inactive disease [13]. By comparison to single-cell transcriptional profiles from sorted murine synovial CD45 + Cd11b + Ly6Gcells [12], significant enrichment of resident macrophage populations as well as non-resident infiltrating populations were identified, as well as antiinflammatory macrophage subpopulations and inhibitory and inflammatory cytokines, indicating that multiple macrophage subtypes and their secreted products may contribute to and perhaps protect against LA pathogenesis.…”

Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus

“…The balance of these SLE-related abnormalities was different in the various ancestral groups, and their prominence was clearly influenced by SoC medications. Despite this, when these influences were considered and mitigated, a set of molecular abnormalities consistent with SLE was discerned, as has been previously suggested (27,33,80). However, the interpretation of perturbations in gene expression profiles in subjects with SLE requires that all the individual influences, including ancestry, drug therapy, and serological manifestations, be considered, as each can have complex and often contradictory effects.…”

Implications of macrophage polarization in autoimmunity

“…M1/M2 macrophage balance has an important role in lupus, as shown by the improvement of the clinical score after M2 macrophage transference . Accordingly, in another lupus animal model (NZB/W F 1 mice) treated with cyclophosphamide, remission has been associated with the presence of M2 macrophages, particularly the M2b subtype .…”