Biology subjects

Martinez-Gallo, M.

Publications and source records attributed to Martinez-Gallo, M..

3 recordsLinked to original sources

bioRxiv2023

Divergent Epigenetic and Transcriptomic Reprogramming of Monocyte Subpopulations in Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by systemic inflammation involving various immune cell types. Monocytes, pivotal in promoting and regulating inflammation in SLE, differentiate from classical monocytes into intermediate monocytes and non-classical monocytes, assuming diverse roles. In this study, we investigated the epigenetic and transcriptomic profiles of these three monocyte subsets in an SLE cohort. In addition to common DNA methylation and transcriptomic alterations, we identified monocyte subset-specific alterations, especially in DNA methylation, which reflect an impact of SLE on the monocyte differentiation process. SLE classical monocytes exhibited a stronger proinflammatory profile, with an interferon signature and were primed for macrophage differentiation. SLE non-classical monocytes displayed a phenotype related to T cell differentiation regulation, and a Th17-promoting phenotype. Changes in monocyte proportions, DNA methylation and expression occurred in relation to disease activity and involved the STAT1 pathway. Integrating bulk datasets with single-cell RNA-seq data of SLE patients further supported the interferon signature in classical monocytes, associating intermediate and non-classical populations with exacerbated complement activation pathways. Our results indicate a subversion of the epigenome and transcriptome in monocyte differentiation toward non-classical subsets in SLE, impacting function, in relation to disease activity and progression.

immunology↗

bioRxiv2020

The JAK2-STAT pathway epigenetically regulates tolerized genes during the first encounter with bacterial antigens

Microbial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hyporesponsiveness to subsequent infections is mainly displayed by monocytes and macrophages. Endotoxin tolerance is generally acquired following a septic episode. In this study, we investigated DNA methylation changes during the acquisition of in vitro tolerance. We identified a set of TET2-mediated demethylation events that are specific to toll-like receptor (TLR) 2 and TLR4 stimulation. Lipopolysaccharide (LPS)-specific demethylation occurs at genomic sites that have low accessibility in quiescent monocytes, concomitantly with the transcriptional activation of many inflammation-related genes, and they are enriched in binding motifs for several signal transducer and activator of transcription (STAT) family members. Indeed, STAT1, STAT3 and STAT5, elements of the JAK2 pathway, are phosphorylated in association with the acquisition of endotoxin tolerance. Inhibition of the JAK2 pathway impairs the activation of tolerized genes on the first encounter with LPS. This is evidence of a crucial role for this pathway in determining the initial response of these genes to bacterial antigens and provides a pharmacological target to prevent exacerbated responses, allowing regulated responses upon subsequent challenges. Finally, we assess the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis.

immunology↗

bioRxiv2019

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although evidences both support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation. HIGM2 naive and memory B cells both display widespread DNA methylation defects, of which approximately 25% of these defects correspond to active events. For genes that undergo active demethylation that is impaired in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naive B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.

immunology↗