Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1β secretion by bronchoalveolar fluid macrophages from asthmatic subjects

Abstract

Background: House dust mite (HDM)-challenged Apoe 2/2 mice display enhanced airway hyperreactivity and mucous cell metaplasia. Objective: We sought to characterize the pathways that induce apolipoprotein E (APOE) expression by bronchoalveolar lavage fluid (BALF) macrophages from asthmatic subjects and identify how APOE regulates IL-1b secretion. Methods: Macrophages were isolated from asthmatic BALF and derived from THP-1 cells and human monocytes. Results: HDM-derived cysteine and serine proteases induced APOE secretion from BALF macrophages through proteaseactivated receptor 2. APOE at concentrations of less than 2.5 nmol/L, which are similar to levels found in epithelial lining fluid from healthy adults, did not induce IL-1b release from BALF macrophages. In contrast, APOE at concentrations of 25 nmol/L or greater induced nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLRP) 3 and pro-IL-1b expression by BALF macrophages, as well as the caspase-1-mediated generation of mature IL-1b secreted from cells. HDM acted synergistically with APOE to both prime and activate the NLRP3 inflammasome. In a murine model of neutrophilic airway inflammation induced by HDM and polyinosinic-polycytidylic acid, APOE reached a concentration of 32 nmol/L in epithelial lining fluid, with associated increases in BALF IL-1b levels. APOE-dependent NLRP3 inflammasome activation in macrophages was primarily mediated through a potassium efflux-dependent mechanism. Conclusion: APOE can function as an endogenous, concentration-dependent pulmonary danger signal that primes and activates the NLPR3 inflammasome in BALF macrophages from asthmatic subjects to secrete IL-1b. This might represent a mechanism through which APOE amplifies pulmonary inflammatory responses when concentrations in the lung are increased to greater than normal levels, which can occur during viral exacerbations of HDM-induced asthma characterized by neutrophilic airway inflammation.

Dementia and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review and meta-analysis

“…( Bonanad et al, 2020 ) Second, patients with dementia were associated with the ApoE e4 genotype. ( Kuo et al, 2020 ) ApoE itself has lipoprotein function and modulates the macrophage pro/anti-inflammatory phenotypes ( Tudorache et al, 2017 ) and is expressed by many cell types in the lung, including macrophages, type I and type II alveolar epithelial cells ( Gordon et al, 2019 ), therefore it is possible that having one or two copies of ApoE4 can increase the risk of having severe COVID-19 infection by robust innate immune response and cytokine storm that results in acute respiratory distress syndrome (ARDS). Third, inflammation also plays an important role in the pathogenesis of dementia.…”

Meeting the Challenge of Identifying New Treatments for Type 2-Low Neutrophilic Asthma

“…APOE activated the NLRP3 inflammasome and IL-1b secretion from ex vivo cultures of asthmatic alveolar Th1/ILC1 IFN-g, CXCL10, SLPI, TNF chestjournal.org macrophages. 29 APOE also induced the secretion of both CXCL5 and IL-8, which have chemoattractant activity toward neutrophils, by ex vivo cultures of asthmatic airway epithelial cells via a TLR4/TAK1/ IKKb/NF-kB/TPL2/JNK signaling pathway. 35 In conclusion, the identification of biomarkers to distinguish endotypes that mediate neutrophilic asthma can guide the development of targeted interventions that are delivered in a precision medicine approach to those subjects in whom the pathway is active (Table 1).…”

“…IL-1b is a proinflammatory cytokine generated by the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome, mainly in monocytes and macrophages, and plays a central role in mediating chestjournal.org innate immunity. 29 Both the NLRP3 inflammasome and IL-1b have been linked to neutrophilic airway inflammation and increased disease severity in severe, steroid-resistant asthma. The concept of targeting IL-1b for neutrophilic asthma has advanced to early-stage clinical trials.…”

Dementia is Associated with Severe Coronavirus Disease 2019 (COVID-19) Infection

“… 6 Second, patients with dementia were associated with the ApoE e4 genotype. 7 ApoE itself has lipoprotein function and modulates the macrophage pro/anti-inflammatory phenotypes 8 and is expressed by many cell types in the lung, including macrophages, type I and type II alveolar epithelial cells 9 , therefore it is possible that having one or two copies of ApoE4 can increase the risk of having severe COVID-19 infection by robust innate immune response and cytokine storm that results in acute respiratory distress syndrome (ARDS). A study by Kuo et al 10 has demonstrated that patients with ApoE e4e4 more likely to have severe COVID-19 infections.…”