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.

Neurodegenerative diseases are characterized by the progressive loss of neurons, synapses, dendrites, and myelin in the central and/or peripheral nervous system. Actual therapeutic options for patients are scarce and merely palliative. Although they affect millions of patients worldwide, the molecular mechanisms underlying these conditions remain unclear. Mitochondrial dysfunction is generally found in neurodegenerative diseases and is believed to be involved in the pathomechanisms of these disorders. Therefore, therapies aiming to improve mitochondrial function are promising approaches for neurodegeneration. Although mitochondrial-targeted treatments are limited, new research findings have unraveled the therapeutic potential of several groups of antibiotics. These drugs possess pleiotropic effects beyond their anti-microbial activity, such as anti-inflammatory or mitochondrial enhancer function. In this review, we will discuss the controversial use of antibiotics as potential therapies in neurodegenerative diseases.

Inflammasomes including those assembled by NLRP1 and NLRP3 regulate the innate immune system by inducing interleukin (IL)-1β 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-1β 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.