Biology subjects

Hudrisier, D.

Publications and source records attributed to Hudrisier, D..

4 recordsLinked to original sources

bioRxiv2026

ST8SIA4-mediated polysialylation is critical for CCR2-driven monocyte egress from the bone marrow

Polysialylation is a rare post-translational protein modification essential for brain development and synaptic plasticity, where it fine-tunes cell-cell and cell-matrix interactions to direct neuronal migration, neurite outgrowth and synaptogenesis. Although polysialic acid is also expressed on circulating leukocytes, its functions in the immune system remain largely unexplored. Guided by analysis of publicly available human genomic data showing that naturally occurring variants of ST8SIA4, which encodes one of the two enzymes that mediate polysialylation, associate with reduced circulating monocyte counts, we investigated the in vivo role of this enzyme in monocyte biology. Using St8sia4-deficient mice, we show that ST8SIA4-dependent polysialylation is essential for CCR2-mediated egress of inflammatory monocytes from the bone marrow at steady state and during Mycobacterium tuberculosis infection. We confirm NCAM1 as the principal polysialylated protein in inflammatory monocytes and demonstrate that Ncam1-deficient mice phenocopy the monocyte defects observed in St8sia4-deficient animals. Mechanistically, loss of ST8SIA4-dependent polysialylation impairs engagement and internalization of the CCR2 ligands CCL2 and CCL7, accompanied by disrupted CCR2 surface organization and extensive cytoskeletal remodeling. Together, these findings identify polysialylation as a previously unrecognized regulator of CCR2 function and monocyte mobilization, with broad implications for immune surveillance and inflammatory responses. Highlights- Human ST8SIA4 variants are associated with reduced blood monocyte and lymphocyte counts and increased risk of SLE. - St8sia4-/- mice exhibit monocytopenia with impaired CCR2-mediated egress of inflammatory monocytes from the bone marrow both at steady state and during Mycobacterium tuberculosis infection. - ST8SIA4 polysialylates NCAM1 (CD56) in inflammatory monocytes, and Ncam1-/- - mice phenocopy the monocytopenia observed in St8sia4-/- mice. - Loss of ST8SIA4 and polysialylation impairs CCR2-mediated binding and endocytosis of CCL2 and CCL7 by monocytes. - Polysialic acid itself does not function as a co-receptor for these chemokines, revealing a new paradigm for its role in immune cell trafficking. - Proper CCR2 surface distribution and function, as well as cytoskeletal organization in inflammatory monocytes, depend on ST8SIA4-mediated polysialylation.

immunology↗

bioRxiv2025

SP140 limits type I interferon-driven pathology, preserving T cell motility and promoting resistance in tuberculosis

CD8+ T cells are elicited during tuberculosis yet how susceptible lung environments shape their maintenance and behavior is unclear. We examined pulmonary T cell responses to Mycobacterium tuberculosis in resistant control and Sp140-/- mice, a model of type I interferon (IFN-I)-driven susceptibility. Resistant mice generated diverse CD8+ effector- and memory-like subsets producing TNF and IFN{gamma}, whereas Sp140-/- mice showed a broad loss of pulmonary CD8+ T cells. Single-cell RNA sequencing revealed altered states in CD8+ T cells from susceptible mice with exhaustion and IFN-I transcriptional programs. IFNAR blockade rescued CD8+ T cell numbers, diversity, cytokine production, reduced bacterial burden and lung pathology, with comparable benefits also valid for CD4+ T cells. Intravital microscopy of infected lungs further showed that T cell dynamics and motility within lesions were restricted under exuberant IFN-I signaling but fully restored by IFNAR blockade. Thus, IFN-I-driven tissue pathology restricts T cell accumulation and motility during tuberculosis. TeaserIn tuberculosis, excessive type I interferon signaling reshapes the lung environment, limiting T cell accumulation and motility within infected lesions.

immunology↗

bioRxiv2021

Metabolic control of type 2 innate lymphoid cells plasticity toward protective type 1-like cells during Mycobacterium tuberculosis infection

Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show that Mycobacterium tuberculosis infection alters the phenotype and function of immature lung ILC2 toward a protective interferon-{gamma}-producing ILC1-like population. This differentiation is controlled by type 1 cytokines and is associated with a glycolytic program involving the transcription factor HIF1. Collectively, our data reveal how tissue-resident ILCs adapt to type 1 inflammation toward a pathogen tailored immune response.

immunology↗

bioRxiv2020

Host-derived lipids from tuberculous pleurisy impair macrophage microbicidal-associated metabolic activity

Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host. Yet, the responsible mechanisms remain elusive. Macrophage activation towards the microbicidal (M1) program depends on the HIF-1 -mediated metabolic shift from oxidative phosphorylation towards glycolysis. Here, we asked whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We exposed M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PE), and found lower glycolytic activity, accompanied by elevated levels of oxidative phosphorylation and bacillary load, compared to controls. The host-derived lipid fraction of TB-PE drove these metabolic alterations. HIF-1 stabilization reverted the effect of TB-PE by restoring M1 metabolism. As a proof-of-concept, Mtb-infected mice with stabilized HIF-1 displayed lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages. Collectively, we demonstrate that host-derived lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1 functions, thereby impairing control of Mtb infection.

immunology↗