Biology subjects

Marquez-Ropero, M.

Publications and source records attributed to Marquez-Ropero, M..

4 recordsLinked to original sources

bioRxiv2025

Metabolic and transcriptional adaptations to phagocytosis in microglia sustain their functionality and regenerative properties

Phagocytosis of apoptotic cells, or efferocytosis, is a tightly regulated process that ensures tissue homeostasis and prevents mounting inflammatory responses. In the brain parenchyma, it is executed by microglia, which are encumbered by large numbers of apoptotic debris generated during development, in adult neurogenic niches, aging, and brain diseases. Emerging evidence suggest that phagocytosis is not limited to garbage disposal, but triggers adaptations in the phagocytes that may have a functional impact. To test it we developed an in vivo model of superphagocytosis induced by low cranial irradiation (LCI, 2Gy) that specifically induced apoptosis in the neurogenic niche of the adult hippocampus, synchronizing microglia in a phagocytic state within 6h and leading to full clearance by 24h. Single cell RNA sequencing and metabolomics revealed an unexpected oxidative stress in post-phagocytic microglia, accompanied by catabolic shutdown, mitochondrial remodeling, increased expression of galectin 3, and production of polyamines that led to cell death and compensatory proliferation. To test whether these changes impaired subsequent microglial phagocytosis, we used a glioblastoma model treated with sequential irradiation to induce tumor cell apoptosis. The phagocytosis efficiency of tumor-associated microglia/macrophages was comparable in the first and second apoptotic challenge, suggesting that the metabolic remodeling induced by phagocytosis was adaptive and destined to sustain their functionality. Finally, we assessed the functional impact of post-phagocytosis adaptations using galectin 3 deficient mice under LCI. We found that the recovery of the neurogenic niche after LCI strongly depended on galectin 3, demonstrating the regenerative capacity of post-phagocytic microglia. Overall, our data unveils the complexity of post-phagocytosis adaptations in microglia, underscoring their unexplored therapeutic potential in brain disorders.

neuroscience↗

bioRxiv2025

MIF-induced CD74+ microglia/macrophages are clinically relevant disease-associated subpopulations in brain metastasis and other CNS disorders

The upregulation of CD74, a chaperone involved in MHC-II antigen processing 1,2, has been broadly reported in virtually all brain disorders analyzed by single-cell RNA sequencing 3-6. However, its expression is usually interpreted as indicative of antigen presentation. In parallel, CD74 expression has also been described in cancer cells across multiple tumor types, but interestingly in glioma its expression has been mainly identified in the microenvironment. However, the functional contribution of CD74 to disease progression in the brain, and specifically in secondary brain tumors, has not been directly addressed. Here we described that, in contrast to what it has been assumed, the presence of CD74+ microglia/macrophages, which is induced by increased levels of interferon gamma in the brain affected by metastases, does not relate to its canonical pathway. Instead, CD74s alternative function as cytokine receptor is pivotal. Rewired by increasing levels of its ligand MIF, produced by proliferating cancer cells, the CD74 receptor, upon binding to this ligand, translocates to the nucleus activating a NF-{kappa}B-dependent program promoting metastasis progression. A brain metastasis-associated CD74 signature involves a more aggressive progression of the local disease in patients, while it has no clinical correlation with the matched primary tumor. Furthermore, we identified the CD74+ myeloid population in additional brain disorders including Alzheimers disease and multiple sclerosis, which shared a pan-disease non-canonical signature with clinical relevance. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreases brain metastases in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. Our findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a novel vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders, guided by a non-invasive molecular strategy.

cancer biology↗

bioRxiv2022

A paracrine circuit of IL-1b/IL-1R1 between myeloid and tumor cells drives glioblastoma progression

Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate and promote glioblastoma growth. Here we discover that glioma cells induce the expression of potent pro-inflammatory cytokine IL-1{beta} in MDM, which engages IL-1R1 in glioma cells, activates NF-{kappa}B pathway, and subsequently leads to the induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1{beta}/IL-1R1 between the tumors and MDM creates an interdependence driving glioblastoma progression. Locally antagonizing IL-1{beta}/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, reduced exhausted CD8+ T cells, and thereby extends the survival of tumor-bearing mice. In contrast to IL-1{beta}, IL-1a exhibits anti-tumor effects. Genetic deletion of Il1a is associated with decreased recruitment of lymphoid cells and loss of interferon (IFN) signaling in various immune populations and subsets of malignant cells. IL-1{beta} antagonism of IL-1{beta} should be considered as an effective anti-glioblastoma therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/486888v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1c99e57org.highwire.dtl.DTLVardef@1ba9d24org.highwire.dtl.DTLVardef@a2c418org.highwire.dtl.DTLVardef@1f8091c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of their intracellular contents. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in mice chronically deficient for two microglial phagocytosis pathways (P2Y12 and MerTK/Axl), but was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of microglial phagocytosis in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia act as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.\n\nGRAPHICAL ABSTRACT

cell biology↗