Researchers here show that signaling related to inflammatory regulation within a cell, undertaken in response to stress, can induce cellular senescence. Preventing the onset of the senescent state in response to some forms of stress may be beneficial, and indeed may be a part of the way in which therapies such as low dose mTOR inhibition can lower the burden of cellular senescence over time. A blanket prevention of senescence is probably a bad idea, as some cells become senescent for good reasons: they are damaged in ways that can produce cancer, or they are assisting in wound healing, for example. But more discriminating sabotage of pro-senescent mechanisms may help to prevent some of the consequences of an aged tissue environment by reducing the pace at which otherwise viable cells become senescent.
Cellular senescence is a cell state characterized by a proliferative cellular arrest, a secretory phenotype, macromolecular damage, and altered metabolism that can be triggered by several different stress mechanisms. Senescent cells produce and secrete a myriad of soluble and insoluble factors, including cytokines, chemokines, proteases, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). More recent evidence proposes that different triggers might induce distinctive SASP subsets with concrete functions. Nonetheless, the SASP has started to incite interest as a potential therapeutic target in disease. Therefore, a better understanding of the molecular machinery regulating the SASP is needed.
Pattern recognition receptors (PRRs) of the innate immune system are molecular sensors that are activated by microbial-derived pathogen-associated molecular patterns (PAMPs) or by damage-associated molecular patterns (DAMPs or alarmins) generated endogenously in cells under certain conditions of stress and damage. Emerging data indicate a close relationship between these PRRs and cellular senescence.
We have previously shown that inflammasomes are critical for the SASP. Inflammasomes are multiprotein platforms that induce the proteolytic activity of the inflammatory protease caspase-1, which activates by proteolytic cleavage the proinflammatory cytokines IL-1β and interleukin-18 (IL-18). The canonical inflammasomes are assembled by PRRs. Alternatively, the related inflammatory caspase-4 and caspase-5 (caspase-11 in mice) function as independent PRRs for cytoplasmic microbial lipopolysaccharide (LPS) activating a noncanonical inflammasome.
Because the mechanism of SASP regulation by inflammasomes remains ill-defined, we decided to define the role of these inflammatory caspases in senescence. We show here that caspase-4 activation by cytoplasmic LPS triggers a senescence phenotype. Moreover, we show here that the caspase-4 noncanonical inflammasome contributes critically to the establishment of the SASP and the reinforcement of the cell cycle arrest program during oncogene-induced senescence. In all, we describe a new and critical function for cytoplasmic sensing by the caspase-4 noncanonical inflammasome in cellular senescence.