Biology subjects

Cordero, M. D.

Publications and source records attributed to Cordero, M. D..

7 recordsLinked to original sources

bioRxiv2026

Human NLRP1 and NLRP3 interact driving inflammation in inflammosomopathies and inflammatory diseases

Inflammasomes are multiprotein complexes that form and activate after exposure to pathogenic microbes and host danger signals that trigger an inflammatory response. Although NLRP1 and NLRP3 inflammasomes share structural similarities and can be activated by similar stimuli, no evidence of heterotypic inflammasome assemblies has been reported. Here, we identify a unique interaction between NLRP1 and NLRP3 in human cells, forming a hybrid inflammasome, to drive inflammation. NLRP1 is essential for this hydrid inflammasome activation and NLRP3-mediated Caspase-1 activation and release of IL-1{beta} and IL-18. The presence of the heterocomplex inflammasome was confirmed in blood samples from patients after kidney transplantation and is associated with inflammatory responses driven by NLRP3 and MEFV mutations that cause inflammasomopathies. Our findings reveal an unexpected level of intricacy in inflammasome composition, pinpointing hybrid targets that may pave the way for innovative pharmacological treatments for inflammatory disorders. Significance StatementPrevious findings showed interactions between NLRP3 and NLRC4 or NLRP3 and NLRP11 showing that would be possible the interaction of the inflammasomes as supercomplexes and not working alone. Now, we show a new inflammasome heterocomplex inflammasome between NLRP1 and NLRP3 which is associated to the inflammatory profile in autoimmune diseases patietns and transplanted patients. These findings could open a new research topic for the design of dual inflammasomes inhibitors.

immunology↗

bioRxiv2024

Human natural killer cells can activate NLRP1 and NLRP3 inflammasomes and drives pyroptosis

Innate immunity relies on inflammasomes as key mediators of host defense, orchestrating the release of pro-inflammatory cytokines and triggering pyroptotic cell death in response to harmful stimuli. Although inflammasome activity has been extensively studied in myeloid cells, its role in natural killer (NK) cells remains underexplored. This study demonstrates that human primary NK cells can functionally activate inflammasomes both in vitro and in vivo, including in patients undergoing organ transplantation. Ex vivo stimulation with nigericin and the dipeptidyl peptidases (DPP) inhibitor Talabostat (Val-boroPro) induces pyroptotic cell death in a subset of NK cells. This is marked by the cleavage and activation of gasdermin D, a lytic pore-forming protein essential for pyroptosis. Accompanying gasdermin D activation, significant levels of lactate dehydrogenase (LDH) and residual amounts of interleukin-18 (IL-18) are released. The detection of activated caspase-4 further indicates that these processes are mediated through non-canonical inflammasome pathways in NK cells. Notably, CD56dim and CD56bright NK cell subsets exhibit distinct responses to pro-inflammatory stimulation. In patients with renal dysfunction, sustained inflammasome activation, particularly involving NLRP1 and NLRP3, is observed in NK cells, with a shift toward a more pro-inflammatory phenotype following kidney transplantation. Single-cell RNA sequencing analyses further reveal persistently elevated expression of caspase-4 and gasdermin-D in transplant recipients experiencing rejection and microvascular inflammation. These findings highlight the underappreciated role of NK cells in inflammasome-driven inflammation, underscoring their importance in both basic research and clinical contexts.

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↗

bioRxiv2022

NEK7 activates the NLRP1 Inflammasome

Inflammasomes including those assembled by NLRP1 and NLRP3 regulate the innate immune system by inducing interleukin (IL)-1{beta} and IL-18 maturation. Inflammasomes are functionally regulated by post-translational modifications such as phosphorylation. The current paradigm posits that NEK7 is the essential and seletive activator of NLRP3; whether this kinase interacts with NLRP3 structurally-related member, NLRP1, has never been explored. Here, we find that NEK7 binds to NLRP1 and promotes its activation independently of NLRP3. IL-1{beta} maturation induced by NLRP1 or NLRP3 inflammasome activators, but not those of the NLRC4 or AIM2 inflammasome is impared in Nek7 deficient cells. This discovery expands the spectrum of NEK7 actions in the regulation of inflammasome pathways.

immunology↗

bioRxiv2021

L-arginine ameliorates defective autophagy in GM2 gangliosidoses by mTOR modulation

Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause fatal and progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by {beta}-hexosaminidase A (HexA) leads to the accumulation of its specific substrate, GM2 ganglioside, in neuronal lysosomes. Despite the development of a florid storage phenotype, the role of autophagy and its regulation by the mammalian target of rapamycin (mTOR) has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay-Sachs and Sandhoff diseases. Pathological autophagosomes, with enhanced expression of the p62/SQSTM1 protein, suggested impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed inappropriately diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities - and immediately suggests an avenue for therapeutic exploration in this cruel disease. We also contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of systemic treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy

cell biology↗

bioRxiv2020

NLRP3 inflammasome inhibition rescues Hutchinson-Gilford Progeria cellular phenotype and extend longevity of an animal model

Inflammation is a hallmark of aging and accelerated aging syndromes. In this context, inflammation has been associated to the pathophysiology of Hutchinson-Gilford progeria syndrome (HGPS). In this study, we report that progeroid skin fibroblasts and animal models present an hyperactivation of the NLRP3-inflammasome complex. High expression of NLRP3 and caspase 1 was also observed in skin fibroblasts from HGPS associated to the nuclei morphology. Lymphoblast from HGPS also showed increased basal levels of NLRP3 and caspase 1 independent to the induction from metabolic factors. Consistent with these results, Zmpste24-/- showed high expression of Nlrp3 and caspase 1 in heart, liver and kidney and reduced levels of Nlrc3, however these changes were not observed in other inflammasomes. We also show that pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved cellular phenotype, significantly extends the lifespan of these progeroid animals and reduced inflammasome-dependent inflammation. These findings suggest the NLRP3-inflammasome comples as a therapeutic approach for patients with HGPS.

immunology↗

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↗