Biology subjects

Verginis, P.

Publications and source records attributed to Verginis, P..

4 recordsLinked to original sources

bioRxiv2025

ACOD1 regulates microglial arginine metabolism and inflammatory responses

Itaconate is produced by inflammatory macrophages and promotes a negative feedback on inflammation. It is synthesized by aconitate decarboxylase 1 (ACOD1) from cis- aconitate, a metabolite of the tricarboxylic acid cycle. Here, we studied the role of ACOD1 in the inflammatory response of microglia, the resident macrophage-like cells of the brain. Similar to macrophages, ACOD1 deficient microglia displayed a stronger inflammatory response to lipopolysaccharide (LPS) compared to their wild type counterparts. The proinflammatory effects of ACOD1 deficiency were associated with reprogramed arginine metabolism entailing enhanced argininosuccinate synthesis at the expense of polyamine synthesis, in a manner that was dependent on ACLY. These findings provide new insights in the immunometabolic role of ACOD1 in inflammatory microglia.

immunology↗

bioRxiv2023

An Immunological Synapse Formation Between T Regulatory Cells and Cancer-Associated Fibroblasts Promotes Tumor Development

Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumor microenvironment, serving diverse functions in tumor progression, invasion, matrix remodeling and resistance to therapy; yet, the precise mechanisms via which CAFs imprint on the anti-tumor immunity remain poorly understood. Extensive molecular characterization revealed an increased heterogeneity in the CAF compartment and proposed an interaction between CAFs and tumor-infiltrating immune cells, which may shape tumor immune evasion. Herein, we describe a synapse formation between -SMA+ CAFs and regulatory T cells (Tregs) in the TME. Foxp3+ Tregs were localized close to -SMA+ CAFs in diverse types of tumor models as well as biopsies from melanoma and colorectal cancer patients. Notably, phenotypically tolerogenic -SMA+ CAFs demonstrated the ability to phagocytose and process tumor antigens, instructing Treg movement arrest, activation and proliferation, in an antigen-specific manner. Of interest, -SMA+ CAFs were characterized by the presence of double-membrane structures, resembling autophagosomes, in their cytoplasm, while analysis of single-cell transcriptomic data pointed autophagy and antigen processing/presentation pathways to be enriched in -SMA-expressing CAF clusters. In a mechanistic view, conditional knockout of the autophagy pathway in -SMA+ CAFs promoted an inflammatory re-programming of CAFs, reduced Treg infiltration, attenuated tumor development, and potentiated the efficacy of immune checkpoint inhibitor immunotherapy. Overall, our findings reveal an immunosuppressive mechanism operating in the TME, which entails the formation of synapses between -SMA+ CAFs and Tregs in an autophagy-dependent fashion and raises the potential for the development of CAF-targeted therapies in cancer. One Sentence Summary-SMA+ Cancer Associated Fibroblasts process and present tumor antigens via autophagy to form immunological synapses with Foxp3+ T regulatory cells in the tumor microenvironment, promoting tumor development.

cancer biology↗

bioRxiv2023

PD-L1 blockade immunotherapy rewires cancer emergency myelopoiesis

Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Herein, we reveal that immunotherapy with PD-L1 blockage antibody (PDL1) in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, from both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice shifting towards an inflammatory state. Functionally, transplantation of HSPCs isolated from PDL1-treated tumor-bearing mice exhibited resistance to cancer-associated myelopoiesis as evident by the generation of reduced frequencies of myeloid-derived suppressor cells (MDSCs) compared to cells from control-treated mice. Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of emergency myelopoiesis.

immunology↗

bioRxiv2021

Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury

Systemic Lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). By employing next-generation sequencing, we compared the gene transcription signatures of CD34+ HSPCs deriving from either the bone marrow or HSPCs patrolling the bloodstream of healthy and individuals with SLE, seeking common transcriptional pathways that may have been modified between steady and disease states. Our findings indicate that circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Non-mobilised, SLE-derived circulating HSPCs demonstrated enhanced engrafting and altered differentiation capacities. Importantly, xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. SLE CD34+ HSPCs homing and engraftment at extramedullary sites such as the spleen and kidneys may participate in peripheral tissue injury.

cell biology↗