The Role of Non-canonical and Canonical Inflammasomes in Inflammaging

Abstract

Neurodegenerative diseases currently affect millions of people worldwide and continues to increase in the expanding elderly population. Neurodegenerative diseases usually involve cognitive decline and are among the top causes of death. Thus, there is a critical need for the development of treatments and preventive strategies for neurodegenerative diseases. One of the risk factors of neurodegeneration is inflammaging, a low level of chronic inflammation due to old age. We have previously shown that the inflammasome contributes to inflammaging in the central nervous system (CNS). The inflammasome is a multiprotein complex of the innate immune response consisting of a sensor protein, apoptosis speck-like protein containing a CARD (ASC), and caspase-1. Our lab has developed a humanized monoclonal antibody against ASC (anti-ASC). Here, we analyzed cortical lysates from young (3 months old), aged (18 months old), and aged anti-ASC treated mice for the expression of canonical and non-canonical inflammasome proteins. We show that the protein levels of NLRP1, ASC, caspase-1, and caspase-8 were elevated in the cortex of aged mice, and that anti-ASC decreased the expression of these proteins, consistent with lower levels of the pro-inflammatory cytokine interleukin (IL)-1β. Additionally, we show that these proteins form a novel NLRP1-caspase-8 non-canonical inflammasome comprised of NLRP1, caspase-8 and ASC. Moreover, these inflammasome proteins were present in neurons in young and aged mice. 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 CNS.

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

“…Inflammation represents cellular defense against stress, which is closely related to the stability of the nervous system. It turns out that chronic low-level inflammation exists in the development of nerve cells and cause imperceptible but accumulatively devastating changes, while acute high-level inflammatory stress directly induces nerve cell dysfunctions or death [ 68 ]. Combining with our previous findings, we put forward a notion in this article that β-arrestin2-biased Drd2 signaling in astrocytes suppress the inflammatory damage caused by cGAS activation due to depressive stress, and UNC9995 treatment can significantly moderate astrocytes inflammatory process and ameliorate depressive behavior (Additional file 2 ).…”

N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro

“…In this line, the expression of inflammasome components, as well as the activation of inflammasome measured as NLRP3/ASC punctate structures in tracheal tissue, was more elevated in B.1.1.7 VOC variant than in B.1 variant and correlated with the CRP and LDH serum values which indicate a more severe inflammation which could be driven by inflammasome activation. Interestingly, aging has been connected with a susceptible elevation of inflammasome activation, namely inflammation [ 34 ], consisting of sustained low levels of chronic inflammation due to old age that could prime and predisposes COVID-19-older patients to an overactivation of the inflammasome, explaining, almost in part, the higher mortality in aged patients. This hypothesis was supported in this work by the fact that NLRP3 expression in airway tissue was positively correlated with the age of patients.…”

Inflammasome activation in traumatic brain injury and Alzheimer's disease

“…Moreover, ASC specks may stimulate and perpetuate inflammation after uptake by neighboring cells through recognition by TLRs. Recent studies by Cyr and colleagues show that increased ASC protein expression in the cortical tissue is associated with the progression of the inflammatory response in aging (inflammaging) [22]. Similarly, Kerr and colleagues showed increased ASC protein expression and speck oligomerization in the lung tissue of mice within 4 hours after brain injury that was associated with lung damage after CNS trauma [6].…”

“…PRR such as Toll-like receptors (TLR) and nucleotide oligomerizing domain (NOD)-like receptors (NLR) facilitate the innate immune system to recognize damage associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs), which induce macrophages to immediately react and shift to a mobile and inflammatory phenotype thus mediating phagocytosis of invaders and the secretion of inflammatory signaling proteins to alert nearby cells of potential harm [12,20]. Similarly, other cells express PRR and recognize DAMPs and PAMPs, triggering activation of the innate immune response, including inflammasomes in neurons [21][22][23][24], astrocytes [25], microglia [11,15] and oligodendrocytes [26].…”

“…Studies involving an anti-ASC drug called IC100 show exciting results in reducing inflammatory activity and improving functional outcomes in murine models of inflammaging, multiple sclerosis, and CNS injury induced acute lung injury [6,22,123].…”