Biology subjects

Mitroulis, I.

Publications and source records attributed to Mitroulis, I..

4 recordsLinked to original sources

bioRxiv2025

In Silico Investigation of the Role of Local and Global Inflammation-Driven Feedback in Myelopoiesis and Clonal Cell Expansion

Chronic inflammation perturbs hematopoietic homeostasis, promoting aberrant myelopoiesis and clonal expansion of mutated stem cells. Here, we develop a mathematical model that integrates both local (bone marrow-intrinsic) and global (systemic/peripheral) inflammation-driven feedback mechanisms to investigate their roles in hematopoietic regulation and disease progression. Our model captures the nonlinear interplay between self-renewal, progenitor proliferation, and inflammatory cues, enabling classification of healthy, myelodysplastic, and leukemic states based on stem cell population dynamics. We show that global inflammatory feedback enhances the resilience of hematopoiesis, while excessive feedback on progenitor cells under chronic inflammation drives instability and clonal dominance. Using sensitivity analysis and parameter space mapping, we identify critical feedback thresholds governing transitions between hematopoietic states and reveal how mutated clones exploit inflammation to outcompete wild-type cells. This systems-level framework offers mechanistic insights into the emergence of myeloid malignancies and provides a computational platform for exploring potential anti-inflammatory therapeutic strategies.

systems biology↗

bioRxiv2025

Exercise induces anti-inflammatory reprogramming in macrophages via Hsp60

Physical activity exerts systemic anti-inflammatory effects and reduces the risk for multiple non-communicable diseases, with 7.2% of all-cause deaths globally being attributed to physical inactivity. However, the cellular and molecular components of the exercise-induced anti-inflammatory effects remain only partly understood. Herein we show that moderate-intensity exercise promotes anti-inflammatory reprograming of macrophages orchestrated by the skeletal muscle cells secretome. Primary bone marrow-derived macrophages (BMDMs) exposed to the secretome of mechanically-loaded myotubes (exercise-conditioned medium, exCM) acquire an anti-inflammatory transcriptional profile and increased reliance on oxidative phosphorylation, as shown by Seahorse real-time cell metabolic analysis, compatible with an M2-like phenotypic switch. Using an unbiased proteomic analysis of the exCM we identify the chaperonin Hsp60 as a key mediator of the anti-inflammatory effects of exercise. Hsp60 expression increases in mechanically loaded myotubes in vitro, in the quadriceps muscle and serum of mice following an 8-week program of moderate-intensity aerobic exercise, as well as in human muscle after resistance training. Importantly, treatment of BMDMs with Hsp60 in vitro recapitulates the exCM-induced transcriptional reprograming, promoting an M2-like phenotype. Taken together, our data highlight Hsp60 as a novel component of the skeletal muscle cell-macrophage crosstalk, providing mechanistic insights into the anti-inflammatory effects of exercise.

physiology↗

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↗