Biology subjects

Arnold, I. C.

Publications and source records attributed to Arnold, I. C..

3 recordsLinked to original sources

bioRxiv2024

Eosinophils restrict CRC metastasis by inhibiting pro-tumorigenic SPP1+ macrophage differentiation

Eosinophils, traditionally associated with allergic responses, have emerged as critical immune modulators in colorectal cancer (CRC). Here, we reveal that eosinophils actively shape the tumor microenvironment and influence metastatic progression. Using comprehensive transcriptomics analysis of human CRC and a murine orthotopic tumor model, we identify a conserved tumor-specific eosinophil signature and activation profile. Despite their declining presence in advanced CRC, eosinophils suppress metastatic dissemination by counteracting the pro-tumorigenic functions of SPP1+ macrophages - a subset linked to immune exclusion and tumor metastasis. Mechanistically, eosinophils respond to tumor-derived signals and inhibit macrophage differentiation into SPP1+ cells. Eosinophil depletion exacerbates peritoneal tumor spread. These findings highlight the pivotal role of eosinophils in restraining late-stage CRC progression and unveil a novel eosinophil-macrophage axis as potential therapeutic targets.

cancer biology↗

bioRxiv2021

Single-cell RNA sequencing unveils intestinal eosinophil development and specialization

Eosinophils are an integral part of the gastrointestinal (GI) immune system that contribute to homeostatic and inflammatory processes. Here, we investigated the existence of functional subsets that carry out specialized tasks in health and disease. We used single-cell transcriptomics and high-dimensional flow cytometry to delineate murine eosinophil subpopulations and their ontogenetic relationship in the steady state and during infection and inflammation. Profiling of eosinophils from bone marrow, blood, spleen and several GI tissues revealed five distinct subsets representing consecutive developmental and maturation stages across organs, each controlled by a specific set of transcription factors. Furthermore, we discovered a highly adapted PD-L1+CD80+ eosinophil subset in the GI tract, characterized by its immune regulatory properties, bactericidal activity upon challenge infection and tissue-protective function during inflammation. Our data provide a framework for the characterization of eosinophil subsets in GI diseases and highlight their crucial contribution to homeostasis, immune regulation and host defense.

immunology↗

bioRxiv2019

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c+ macrophage phenotype

Mononuclear phagocytes (MNPs) play a key role in maintaining intestinal homeostasis but also in triggering immunopathology in response to acute microbial stimulation, which induces the recruitment of masses of Ly6Chi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon Regulatory Factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state, but ameliorates immunopathology during Helicobacter hepaticus induced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single cell RNA-sequencing approaches we compare the differentiation trajectories of wild type and IRF5 deficient monocytes in a shared inflammatory environment and demonstrate that IRF5 stipulates a choice in monocyte differentiation towards macrophages. Specifically, IRF5 promotes the generation of pathogenic CD11c+ macrophages and controls the production of inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional controller of pathogenic monocyte differentiation in the gut.

immunology↗