Biology subjects

Astorga-Gamaza, A.

Publications and source records attributed to Astorga-Gamaza, A..

3 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↗

bioRxiv2022

Identification of HIV-Reservoir Cells with Reduced Susceptibility to Antibody-Dependent Immune Response

HIV establishes a persistent infection in heterogeneous cell reservoirs, which can be maintained by different mechanisms including cellular proliferation, and represent the main obstacle to curing the infection. The expression of the Fc{gamma} receptor CD32 has been identified as a marker of the active cell reservoirs in people on antiretroviral therapy, but if its expression has any role in conferring advantage for viral persistence is unknown. Here, we report that HIV-infected cells expressing CD32 have reduced susceptibility to natural killer (NK) antibody-dependent cell cytotoxicity (ADCC) by a mechanism compatible with the suboptimal binding of HIV-specific antibodies. Infected CD32 cells have increased proliferative capacity in the presence of immune complexes, and are more resistant to strategies directed to potentiate NK function. Remarkably, reactivation of the latent reservoir from antiretroviral-treated people living with HIV increases the pool of infected CD32 cells, which are largely resistant to the ADCC immune mechanism. Thus, we report the existence of reservoir cells that evade part of the NK immune response through the expression of CD32. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗