Biology subjects

Gallardo-Orihuela, A.

Publications and source records attributed to Gallardo-Orihuela, A..

3 recordsLinked to original sources

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↗

bioRxiv2023

Retinal affectation in Huntington's disease mouse models concurs with a local innate immune response

Huntingtons disease (HD) is a devastating disorder caused by aberrant expansion of CAG repeats in the HTT gene. Striatal dysfunction has been widely studied in HD mouse models. However, cumulative evidence indicates that the retina can also be functionally altered with consequences for visual function and circadian rhythms. The retina is the most exposed part of the central nervous system that can be used for monitoring the health status of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we linked the retinal alterations with those in the inner brain. We confirmed the malfunction of the R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum, indicating a profound retinal affectation in HD. Tissue-enriched genes were downregulated in both areas, but a neuroinflammation signature was specifically induced in the R6/1 retina due to glial activation that was reminiscent of the situation in HD patients brains. These phenomena were confirmed in the zQ175 strain, and were accompanied by a differential impairment of the autophagy system between both tissues. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD.

neuroscience↗

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↗