Biology subjects

Hurtado-Navarro, L.

Publications and source records attributed to Hurtado-Navarro, L..

4 recordsLinked to original sources

bioRxiv2025

The inflammasome adaptor protein ASC triggers immunometabolic dysregulation induced by dysbiosis during obesity

The inflammasomes are a component of the innate immune system that induce inflammation after activation by danger and pathogen signals, this process is of extreme importance in the gut, where high-saturated fat diets modulate inflammasome activity resulting in dysbiosis and inflammation. In this work, we found that the common inflammasome adaptor protein, apoptosis speck-like protein with a caspase activation domain (ASC), is essential for the development of metabolic dysregulation during high fat diet. ASC-deficient mice (Pycard-/-) presented lower weight gain and improved glucose tolerance, enhancing metabolism, and reducing inflammation in both intestine and liver. The extracellular administration of ASC oligomers to Pycard-/- mice partially rescued dysbiosis, intestinal metabolism and inflammation. Therefore, ASC presents intracellular functions activating the inflammasome, as well as extracellular function as an oligomer during metabolic dysregulation, emerging ASC as a potential drug target beneficial to treat obesity and metabolism-associated liver diseases.

immunology↗

bioRxiv2024

Gasdermin D mediates a fast transient release of ATP after NLRP3 inflammasome activation before ninjurin 1-induced lytic cell death

Pyroptosis is a lytic cell death triggered by the cleavage of gasdermin (GSDM) proteins and subsequent pore formation by the N-terminal domain oligomerization in the plasma membrane. GSDMD is cleaved by caspase-1/-4/-5/-11 upon inflammasome activation and mediates IL-1{beta} and IL-18 release. GSDMD pores favors ninjurin-1 (NINJ1) induced plasma membrane rupture and cell death. Here, we demonstrate that GSDMD mediates early ATP release upon NLRP3 inflammasome activation independently of NINJ1, occurring before IL-1{beta} release and cell death and constituting an early danger signal. The release of ATP is a transient signal terminated before the cells continue to permeabilize and die. The different N-terminal of GSDMA to E are also able to release ATP and induce monocyte migration towards pyroptotic cells. This study reveals ATP release as an early, and transient danger signal depending on GSDMD plasma membrane permeabilization, independently of the late stages of lytic cell death.

immunology↗

bioRxiv2022

Soluble P2X7 receptor is elevated in the plasma of COVID-19 patients and correlates with disease severity

Inflammation is a tightly coordinated response against bacterial and viral infections, triggered by the production of pro-inflammatory cytokines. SARS-CoV-2 infection induces COVID-19 disease, characterized by an inflammatory response mediated through the activation of the NLRP3 inflammasome, which results in the production of IL-1{beta} and IL-18 along with pyroptotic cell death. The NLRP3 inflammasome could be also triggered by sterile danger signals such as extracellular ATP triggering the purinergic P2X7 receptor. Severe inflammation in the lungs of SARS-CoV-2 infected individuals is associated with pneumonia, hypoxia and acute respiratory distress syndrome, these being the causes of death associated with COVID-19. Both the P2X7 receptor and NLRP3 have been considered as potential pharmacological targets for treating inflammation in COVID-19. However, there is no experimental evidence of the involvement of the P2X7 receptor during COVID-19 disease. In the present study we determined the concentration of different cytokines and the P2X7 receptor in the plasma of COVID-19 patients and found that along with the increase in IL-6, IL-18 and the IL-1 receptor antagonist in the plasma of COVID-19 patients, there was also an increase in the purinergic P2X7 receptor. Increase in COVID-19 severity and C-reactive protein concentration positively correlated with increased concentration of the P2X7 receptor in the plasma, but not with IL-18 cytokine. The P2X7 receptor was found in the supernatant of human peripheral blood mononuclear cells after inflammasome activation. Therefore, our data suggest that determining levels of the P2X7 receptor in the plasma could be a novel biomarker of COVID-19 severity.

immunology↗

bioRxiv2022

Ornithine Lipid Activates Both TLR4 and the non-canonical NLRP3 Inflammasome.

Myeloid cells recognise Gram-negative bacterial lipopolysaccharides (LPS). LPS recognition triggers inflammatory reactions through Toll-like receptor 4 (TLR4) and primes the cells for inflammasome activation. In phosphate-depleted environments, bacteria cannot produce LPS. Instead, they increase their synthesis of ornithine lipid (OL), which is constitutively present in some pathogenic Gram-negative and -positive bacteria but absent in commensals. OL is implicated in bacterial pathogenicity, but the mechanism is unclear. Using primary murine macrophages and human peripheral blood mononuclear cells, we identify OL as a partial TLR4 agonist and an NLRP3 inflammasome activator. For this, OL directly activates TLR4 and indirectly activates NLRP3 in a potassium-efflux-dependent manner. OL also upregulates the expression of NLRP3 and pro-IL-1{beta} and induces cytokine secretion in primed and unprimed cells. By contrast, in the presence of LPS, OL functions as a partial TLR4 antagonist; LPS-induced TLR4 activation and inflammasome priming are inhibited by OL, leading to reduced TNF and IL-1{beta} secretion. We thus suggest that in phosphate-depleted environments, OL replaces LPS bacterial immunogenicity while constitutively present OL may allow bacteria to escape immune surveillance.

immunology↗