Biology subjects

Ryffel, B.

Publications and source records attributed to Ryffel, B..

6 recordsLinked to original sources

bioRxiv2026

Extracellular Vesicle-Enriched Secretome from Mesenchymal Stromal Cells Protects Against Chemically, Particulate-, and Ischemia-Induced Innate-Immunity Induced Inflammation

Mesenchymal stromal cells (MSCs) are multipotent cells with well-established regenerative and immunomodulatory properties, making them promising candidates for the treatment of inflammatory diseases. However, the therapeutic effects of MSCs are largely mediated by their secretome, particularly extracellular vesicles (EVs), which deliver bioactive molecules capable of modulating inflammatory responses. We generated an extracellular vesicle-enriched secretome (EVES) from MSCs under scalable, Good Manufacturing Practice (GMP)-compliant conditions and assessed its therapeutic efficacy in diverse disease models, including lung inflammation and kidney injury induced by distinct innate immune stimuli. EVES was isolated from the secretome of umbilical cord blood-derived MSCs cultured in a chemically defined medium. In vitro, EVES significantly and dose-dependently attenuated cytokine release from airway epithelial cells and macrophages stimulated with inflammatory agents such as lipopolysaccharide or reactive particles. In murine models of lung inflammation, EVES reduced neutrophil infiltration and suppressed multiple cytokines and chemokines in a dose-dependent manner. In models of kidney injury, EVES enhanced tubular epithelial cell proliferation, improved renal histology, and markedly reduced tubular necrosis following ischemia-reperfusion injury. Collectively, these findings demonstrate that MSC-derived EVES exhibits robust and broad-spectrum therapeutic activity across multiple disease contexts driven by innate immune activation, supporting its potential as a scalable, cell-free therapeutic platform.

cell biology↗

bioRxiv2025

Maternal type 2 immunity promotes a microchimeric transfer of systemic type 2 immunity to offspring.

During maternity mothers undergo an immune pivot to a type 2 immune phenotype which is independent of any antigen experience. In this study we present this maternal Type 2 immunity as a key enabler of optimal maternally-driven microchimeric transfer of immunity to helminth infection in offspring. To demonstrate that maternal type 2 immunity dictates offspring immunity we nursed wildtype (WT) offspring on WT or IL-4R-/- foster mothers. WT offspring nursed on IL-4Ra-/- mothers acquired a reduced type 2 immune signature compared to WT offspring nursed on WT mothers. This demonstrated maternal IL-4R imprints type 2 immunity in offspring. This increased type 2 immunity in offspring related to a maternal IL-4R dependent increased frequency of maternal microchimeric cells (MMc) being detected in offspring. Higher worm burdens were detected in offspring nursed on IL-4R-/- mothers, demonstrating that an antigen independent promotion of maternal type 2 immunity provides offspring with protective immunity against a helminth infection. To establish the contribution of increased MMc in offspring nursed on WT mothers in the control of infection, we undertook an antibody mediated depletion of MMc cells in WT offspring. This MMc depletion impaired the control of infection and reduced the magnitude of offspring type 2 immune response against a helminth infection. These findings present antigen independent maternal IL-4R driven type 2 immunity during pregnancy as critical for imparting a profound immune influence via MMc on offspring immunity to infection.

immunology↗

bioRxiv2023

NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype

Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as the senescence-associated secretory phenotype (SASP). Here, we present evidence that the inflammasome sensor, NLRP1, is a key mediator of senescence induced by irradiation both in vitro and in vivo. The NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP in Gasdermin D (GSDMD)-dependent manner as these responses are reduced in conditions of NLRP1 insufficiency or GSDMD inhibition. Mechanistically, the NLRP1 inflammasome is activated downstream of the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS) in response to genomic damage. These findings provide a rationale for inhibiting the NLRP1 inflammasome-GSDMD axis to treat senescence-driven disorders.

immunology↗

bioRxiv2020

Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates PD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-{gamma} by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.

cancer biology↗

bioRxiv2020

Inhibition of the NLRP3 inflammasome prevents ovarian aging

Inflammation is a hallmark of many processes during aging and reproductive physiology, negatively affecting female fertility. The goal of this study was to evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in female WT mice during reproductive aging. High expression of NLRP3, caspase 1 and IL-1{beta} was also observed in granulosa cells from patients with primary ovarian insufficiency. Ablation of the NLRP3 inflammasome improved the survival and pregnancy rates in mice, increased hormonal levels of AMH, a biochemical marker of ovarian reserve, and autophagy rates in ovarian tissue. Deficiency of the NLRP3 inflammasome also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3-/- mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.

immunology↗

bioRxiv2019

Muc5b-deficient mice develop early histological lung abnormalities

Gel-forming mucins are the main organic component responsible for physical properties of the mucus hydrogels. While numerous biological functions of these mucins are well documented, specific physiological functions of each mucin are largely unknown. To investigate in vivo functions of the gel-forming mucin Muc5b, which is with Muc5ac the major secreted airway mucin, we generated mice in which Muc5b was disrupted and maintained in the absence of environmental stress. Adult Muc5b-deficient mice displayed bronchial hyperplasia and metaplasia, interstitial thickening, alveolar collapse, immune cell infiltrates, fragmented and disorganized elastin fibers and collagen deposits that were for approximately one fifth of mice associated with altered pulmonary function leading to respiratory failure. These lung abnormalities start early in life, as demonstrated for one fourth 2-day-old Muc5b-deficient pups. Thus, the mouse mucin Muc5b is essential for maintaining normal lung function.

physiology↗