Therapies capable of reducing systemic inflammation are at present quite blunt, largely interfering in signaling that is needed for necessary short-term inflammation as well as that involved in excessive, unresolved inflammation. This has negative effects on immune function, leading to vulnerability to pathogens, for example. There is the hope that targeting the function of inflammasomes, protein complexes involved in the mechanisms of the immune response, will prove to be somewhat more selective for unwanted inflammation. This is likely not the final destination for the desired goal of only eliminating excess inflammation, however.
Aging is a significant risk factor for the development of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Inflammation also plays a role in the development of neurodegenerative diseases. Inflammaging, a low level of chronic inflammation that occurs due to old age, is a normal part of the aging process. It has been shown that the inflammasome contributes to age-related inflammation and development of neurodegenerative diseases. Thus, the inflammasome is a potential therapeutic target to ameliorate inflammaging and to prevent and/or treat neurodegenerative diseases.
In this study, we show the anti-inflammatory effects of anti-ASC, a monoclonal antibody against ASC, in the cortex of aged mice. We found that protein levels of IL-1β, ASC, caspase-1, and NLRP1 were significantly elevated in the cortex of aged mice and that anti-ASC treatment inhibits the protein levels of these inflammasome signaling proteins. ASC speck formation was examined and protein levels of ASC specks were increased in old age and anti-ASC inhibits the formation of ASC specks. Moreover, we investigated the protein levels of the non-canonical inflammasome proteins caspase-8 and caspase-11. We found that caspase-8 was also elevated in the cortex of aged mice and that anti-ASC decreased the protein levels of this protein. However, we did not see any significant differences between young and aged mice in the protein levels of caspase-11.
Together, these results indicate that a novel NLRP1-caspase-8 non-canonical inflammasome is present in the cortex of mice and that anti-ASC is a potential therapeutic to decrease inflammasome-mediated inflammaging in the central nervous system.