Biology subjects

Herrero, C.

Publications and source records attributed to Herrero, C..

3 recordsLinked to original sources

bioRxiv2026

MAFB and MAF cooperatively orchestrate human anti-inflammatory macrophage identity via autocrine Interleukin-10

Macrophage lineage identity is governed by intricate transcriptional networks. Although the large MAF basic region-leucine zipper (bZIP) transcription factors MAFB and MAF are critical regulators of anti-inflammatory programs, their molecular coordination and non-redundant contributions within human macrophages remain poorly defined. Here, utilizing integrated proteomic, transcriptomic, and epigenomic profiling, we demonstrate that endogenous MAFB and MAF physically associate to form a stable heterodimeric complex on chromatin in human M-CSF-dependent monocyte-derived macrophages (M-Mac). Genome-wide CUT&Tag mapping reveals a hierarchical epigenomic architecture in which MAFB acts as the primary global anchor of M-Mac identity, whereas MAF provides localized transcriptional tuning. Mechanistically, both factors directly bind the IL10 locus, but functional IL-10 expression is primarily driven by MAFB. Neutralizing antibody assays reveal that endogenously produced IL-10 establishes an obligate autocrine feedback loop mandatory for both the initial acquisition and the maintenance of the M-Mac anti-inflammatory profile. Functionally, MAFB and MAF exert non-redundant control over core macrophage effectors: MAFB dictates apoptotic cell efferocytosis amd T cell activation, whereas MAF modulates phagocytosis, and acts as a brake suppressing acute pro-inflammatory cytokine/chemokine hyper-induction. Together, these findings establish a comprehensive molecular blueprint of how MAFB and MAF cooperatively fine-tune human monocyte-derived macrophage identity and functional plasticity.

immunology↗

bioRxiv2026

Aryl hydrocarbon receptor (AhR) restrains the maintenance and acquisition of the anti-inflammatory identity of monocyte-derived macrophages.

The Aryl hydrocarbon receptor (AhR) is an essential environmental sensor bridging metabolic cues with immune regulation, yet its precise role in defining human monocyte-derived macrophage identity remains unclear. Here, we demonstrate that AhR functions as a critical transcriptional rheostat that selectively restrains the anti-inflammatory and pro-fibrotic identity of M-CSF-dependent monocyte-derived macrophages (M-Mac). Integrated ChIP-Seq and transcriptomic profiling revealed that AhR activity is enriched in M-Mac in a MAFB-dependent manner, directly occupying regulatory regions of core M-Mac identity genes, including CD163, LGMN, and IL10. Unexpectedly, siRNA-mediated knockdown and CRISPR/Cas9 ablation demonstrated that AhR primarily functions as a repressor; its deficiency accelerated and exacerbated the acquisition of a "resident-like" (LYVE1+/FOLR2+) and pro-fibrotic phenotype. Functionally, AhR restricted the M-Mac anti-inflammatory response to TLR7 ligation, and limited an overly tolerogenic profile during M-Mac-driven T-cell responses. Pharmacological modulation using the endogenous ligand FICZ and the antagonist SR1 confirmed that AhR activity limits the magnitude of the MAFB-driven program and the autocrine IL-10 signaling axis. Collectively, these findings establish AhR as a fundamental checkpoint that prevents macrophages from acquiring an excessive anti-inflammatory state, thereby ensuring balanced responses essential for tissue homeostasis and immune surveillance.

immunology↗

bioRxiv2024

Re-programming of GM-CSF-dependent alveolar macrophages through GSK3 activity modulation

Monocyte-derived macrophages recruited into inflamed tissues can acquire an array of functional states depending on the extracellular environment. Since the anti-inflammatory/pro-fibrotic macrophage profile is determined by MAFB, whose activity/protein levels are regulated by GSK3, we addressed the macrophage re-programming potential of GSK3 modulation. GM-CSF-dependent (GM-MO) and M-CSF-dependent monocyte-derived macrophages (M-MO) exhibited distinct levels of inactive GSK3, and inhibiting GSK3 in GM-MO led to acquisition of transcriptional, phenotypic and functional properties characteristic of M-MO (enhanced expression of IL-10 and monocyte-recruiting factors, and higher efferocytosis). These re-programming effects were also observed upon GSK3/{beta} knockdown, and through GSK3 inhibition in ex vivo isolated human alveolar macrophages (AMO). Notably, GSK3 downmodulation potentiated the transcriptional signature of Interstitial Macrophages (IMO) while suppressed the AMO-specific gene profile. Indeed, heightened levels of inactive GSK3 and MAFB-dependent proteins were observed in severe COVID-19 patients lung macrophages, highlighting the GSK3-MAFB axis as a therapeutic target for macrophage re-programming.

immunology↗