Age-induced NLRP3 Inflammasome Over-activation Increases Lethality of SARS-CoV-2 Pneumonia in Elderly Patients

Abstract

Age is one of the most important prognostic factors associated to lethality in SARS-CoV-2 infection. In multivariate analysis, advanced age was an independent risk factor for death. Recent studies suggest a role for the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome activation in lung inflammation and fibrosis in SARS-CoV and SARS-CoV-2 infections. Increased NLRP3/ apoptosis-associated speck-like protein (ASC) mRNA expression and increased caspase-1 activity, have been observed in aged lung, provoking increased and heightened expression levels of mature Interleukin (IL)-1β and IL-18 in aged individuals. Aged individuals have a basal predisposition to overreact to infection, displaying an increased hyper-inflammatory cascade, that seems not to be fully physiologically controlled. NLRP3 inflammasome is overactivated in aged individuals, through deficient mitochondrial functioning, increased mitochondrial Reactive Oxigen Species (mtROS) and/or mitochondrial (mt)DNA, leading to a hyper-response of classically activated macrophages and subsequent increases in IL-1 β. This NLRP3 over-activated status in elderly individuals, is also observed in telomere dysfunctional mice models. In our opinion, the NLRP3 inflammasome plays a central role in the increased lethality observed in elderly patients infected by COVID-19. Strategies blocking inflammasome would deserve to be studied.

COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception—A Systematic Review

“…The neuronal cell death, which can be attributed to the NLRP3 inflammasome activation, has also been shown to be reversible with immunoglobulin in 3-month-old mice stroke models ( 65 ). However, in patients with impaired immune responses, such as the elderly, there is an unprecedented activation of the NLRP3 inflammasome coupled with mitochondrial dysfunction and increased proportions of the mitochondrial reactive oxygen species, which further worsen tissue damage and initiate cell death ( 66 ). In patients with obesity and diabetes in which NLRP3 inflammasomes are already basally activated, and the immune responses are suboptimal, viral-induced activation of the former may worsen a preexisting chronic inflammatory state ( 67 ).…”

“…In patients with stroke, it has been shown that the NLRP3 inflammasome plays a significant role in cerebral atherogenesis by similar activation of the immune system and increase in macrophages, neutrophils, lymphocytes, and vascular smooth muscle cell, which also play an important role in plaque instability (65)(66)(67). The neuronal cell death, which can be attributed to the NLRP3 inflammasome activation, has also been shown to be reversible with immunoglobulin in 3-month-old mice stroke models (65).…”

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

“…Innate immune receptor activation or inactivation has not been studied extensively for severe COVID-19-associated ARDS, but consistent evidence exists for the activation of TLR4 [ 76 , 77 ], TLR7 [ 78 ] and NLRP3 [ 79 , 80 , 81 ]. Conversely, increased levels of NR3C1, an NLRP3 antagonist, decreased the COVID-19 severity [ 82 ].…”

The Impact of Polyphenols-Based Diet on the Inflammatory Profile in COVID-19 Elderly and Obese Patients

“…Indeed, patients with a reduced immune capacity demonstrated a dysregulated NLRP3 inflammasome activity, which results in severe COVID-19 with tissue damage and a cytokine storm ( van den Berg and te Velde, 2020 ). Considering that NLRP3 is frequently over-activated in elderly individuals, it is believed that the NLRP3 inflammasome plays a central role in the increased lethality observed in aged COVID-19 patients ( Lara et al, 2020 ).…”