Biology subjects

Perez-Oliva, A. B.

Publications and source records attributed to Perez-Oliva, A. B..

3 recordsLinked to original sources

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↗

bioRxiv2024

NLRP1 is activated by palmitic acid and induced in human metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent cause of liver disease worldwide. This progressive condition ranges from simple steatosis to a more advanced stage, known as metabolic dysfunction-associated steatohepatitis (MASH), which is characterized by inflammation, hepatocellular ballooning, and hepatic steatosis. Several studies have demonstrated the involvement of inflammasomes in MASH development. Recently, the NLRP1 inflammasome has gained attention as an important sensor in various human inflammatory conditions, though its role in metabolic diseases like MASLD remains unclear. In this study, we identified significantly higher mRNA and protein levels of NLRP1 in liver samples from patients with MASH compared to those with normal or steatotic livers. Furthermore, NLRP1 mRNA levels correlated with hepatic palmitic acid (PA) levels. We also showed that NLRP1 inflammasome expression is mediated by PA in both human HepG2 cells and human liver organoids. Importantly, we found that NLRP1 was activated by PA, but not by other saturated fatty acids like myristic acid, and that PA-induced NLRP1 activation was inhibited by oleic acid. These findings uncover a previously unknown role of the hepatic NLRP1 inflammasome in the human liver. However, further research is needed to fully understand the complex interactions between NLRP1, inflammation, and metabolic processes in the development of MASLD.

molecular biology↗

bioRxiv2021

NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos

Several studies have revealed a correlation between chronic inflammation and NAD+ metabolism but the precise mechanism involved is unknown. Here we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly ADP-ribose (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases and reactive oxygen species (ROS) scavenging, all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of both NAMPT amounts and PARP activity was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death. HighlightsO_LINAMPT inhibition alleviates inflammation in zebrafish and human epidermis organoid models of psoriasis. C_LIO_LINADPH oxidase-derived ROS mediates keratinocyte DNA damage and Parp1 overactivation. C_LIO_LIInhibition of parthanatos cell death phenocopies the effects of NAMPT inhibition in zebrafish and human psoriasis models. C_LIO_LINAMPT and PAR metabolism is altered in psoriasis patients. C_LI

immunology↗