Biology subjects

Lefrancais, E.

Publications and source records attributed to Lefrancais, E..

4 recordsLinked to original sources

bioRxiv2025

The alarmin Interleukin-33 modulates platelet proteome, function and biogenesis

Platelets, traditionally recognized for their involvement in hemostasis and wound healing, also play a central role in immune regulation and inflammation. Their function and production adapt in response to inflammatory cues such as cytokines and danger-associated molecular patterns. Interleukin-33 (IL-33), an alarmin released during tissue damage, particularly in lung inflammation, has been implicated in influencing platelet biology, though its exact effects remain poorly understood. To clarify IL-33s role, we examined its impact on platelet production, proteome, adhesion, secretion, and aggregation using platelets from IL-33-deficient (IL-33KO) mice and IL-33 stimulation in vivo. Our results reveal that while platelets themselves do not express IL-33, platelets isolated from IL-33KO mice display altered proteomic signatures and reduced adhesion to fibrinogen, podoplanin, and laminin, alongside impaired thrombus formation under shear stress. IL-33 administration in vivo led to proteomic remodeling characterized by increased expression of inflammatory proteins, as well as changes in platelet morphology, including increased size, typically associated with de novo production. Using lung intravital microscopy, we visualized platelet fragmentation within the lung vasculature in real time, and observed enhanced fragmentation following IL-33 stimulation. Interestingly, ST2, the receptor for IL-33, is expressed in subsets of mouse and human megakaryocytes and hematopoietic progenitors, particularly those involved in a non-canonical pathway of thrombopoiesis that enables the rapid replenishment of platelets during inflammation, infection, and aging. Together, these findings identify IL-33 as a pivotal regulator of platelet function and production, linking inflammatory signaling to the dynamic regulation of thrombopoiesis. Key PointsIL-33 impacts platelet inflammation-related proteins and adhesion IL-33 receptor is expressed by subsets of MK progenitors in mouse and human

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

Pseudomonas aeruginosa infection reveals a Caspase-1-dependent neutrophil pyroptosis pathway that restrains damaging Histone release

Multiple neutrophil death programs contribute to host defense against infections. Although expressing all necessary components, neutrophils specifically fail to undergo pyroptosis, a lytic form of cell death triggered by the activation of the pro-inflammatory complex inflammasome. In the light of the arm race, we hypothesized that intrinsic neutrophil pyroptosis resistance might be bypassed in response to specific microbial species. We show that Pseudomonas aeruginosa (P. aeruginosa) stimulates Caspase-1-dependent pyroptosis in human and murine neutrophils. Mechanistically, activated NLRC4 inflammasome supports Caspase-1-driven Gasdermin-D (GSDMD) activation, IL-1{beta} cytokine release and neutrophil pyroptosis. Furthermore, GSDMD activates Peptidyl Arginine Deaminase-4 which drives an "incomplete NETosis" where neutrophil DNA fills the cell cytosol but fails crossing plasma membrane. Finally, we show that neutrophil Caspase-1 account for IL-1{beta} production and contributes to various P. aeruginosa strains spread in mice. Overall, we demonstrate that neutrophils are fully competent for Caspase-1-dependent pyroptosis, which drives an unsuspected "incomplete NETosis". SummaryNeutrophils play an essential roles against infections. Although multiple neutrophil death programs contribute to host defense against infections, they fail to undergo pyroptosis, a pro-inflammatory form of cell death. Upon Infections, pyroptosis can be induced in macrophages or epithelial cells upon activation of pro-inflammatory complexes, inflammasomes that trigger Caspase-1-driven Gasdermin dependent plasma membrane lysis. In the light of host-microbe interactions, we hypothesized that yet to find microbial species might hold the capacity to overcome neutrophil resistance to inflammasome-driven pyroptosis. Among several bacterial species, we describe that the bacterium Pseudomonas aeruginosa specifically engages the NLRC4 inflammasome, which promotes Caspase-1-dependent Gasdermin-D activation and subsequent neutrophil pyroptosis. Furthermore, inflammasome-driven pyroptosis leads to DNA decondensation and expansion into the host cell cytosol but not to the so called Neutrophil Extracellular Trap (NET) release as DNA fails breaching the plasma membrane. Finally, in vivo P. aeruginosa infections highlight that Caspase-1-driven neutrophil pyroptosis is functional and is detrimental upon P. aeruginosa infection. Altogether, our results unexpectedly underline neutrophil competence for Caspase-1-dependent pyroptosis, a process that contributes to host susceptibility to P. aeruginosa infection.

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↗