Inhibiting the NLRP1 Inflammasome Reduces the Senescence-Associated Secretory Phenotype
A sizable portion of the chronic inflammation of aging is produced by the growing presence of senescent cells in tissues throughout the body. Senescent cells secrete a mix of pro-growth, pro-inflammatory signals (the senescence-associated secretory phenotype, SASP), useful when present in the short-term in the context of wound healing and suppression of cancer risk resulting from cell damage. When sustained over the long-term, however, this signaling becomes highly disruptive to tissue structure and function. The inflammatory mechanisms inside senescent cells that produce pro-inflammatory components of the SASP include the same mechanisms that operate in normal cells in response to inflammatory stimuli. It is therefore possible that targeted inhibition of regulatory genes and proteins could reduce the SASP.
Today's open access paper is one example of many lines of work that aim to understand how exactly the inflammatory component of the SASP arises. The authors identify the NLRP1 inflammasome as important, as inhibition diminishes the SASP. When it comes to new approaches to suppress inflammation, a great many groups are looking at inflammasomes in cells as a potential point of intervention. It is an open question as to whether this is going to be any better in practice than existing approaches (such as TNF inhibitors) that target important pro-inflammatory signal molecules. The problem with suppressing a target of this nature is that it disrupts desirable, short-term inflammation, needed for the normal immune response to operate, in addition to the undesirable chronic inflammation.
NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype
Aging generates specific changes associated with a process called cellular senescence. This permanent state of cell cycle arrest promotes tissue remodelling during development but leads to the declined tissue regenerative potential and function after injury, and activates inflammation and tumorigenesis in aged organisms. Senescence promotes the production of cytokines, chemokines, proteases, and growth factors some of which are known as senescence-associated secretory phenotype (SASP). Recent studies demonstrates that chromatin is instrumental in regulating SASP and inflammation through the innate immune cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) which can be activated upon DNA sensing.
Inflammasomes are intracellular protein complexes involved in almost all human aging-associated complications such as cancer, cardiovascular, metabolic, and neurodegenerative diseases through the production of interleukin-1β (IL-1β) and IL-18. These protein platforms comprise sensing proteins of the NOD-like receptor (NLR) family, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and procaspase-1. Upon sensing of pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS), some NLRs such as NLRP3 and NLRP1 to some extent associate with ASC, a response that leads to the recruitment and activation of the cysteine protease, caspase-1. Active caspase-1 cleaves pro-IL-1β, pro-IL-18, and GSDMD, thereby facilitating the secretion of IL-1β and IL-18 through plasma membrane pores formed by the N-terminal fragments of GSDMD. These pores can also release IL-1α and cause pyroptosis. Despite scientific advances in the biology of the NLRP1 and NLRP3 inflammasomes, the role that these proteins play in senescence remain controversial.
Irradiation of cells or tissues is a widely used model of stress-induced senescence, which we used to determine the role of the NLRP1 and NLRP3 inflammasomes in this process. We found that irradiation induced the expression of NLRP1, NLRP3, and SASP. Notably, inhibition of the NLRP1 inflammasome but not NLRP3 inflammasome attenuated the expression of senescence markers, responses that were GSDMD- and cGAS-dependent.