Inflammasome Adaptor ASC Is Highly Elevated in Lung Over Plasma and Relates to Inflammation and Lung Diffusion in the Absence of Speck Formation

Autor: Mikhail A. Gavrilin, Christian C. McAndrew, Evan R. Prather, MuChun Tsai, Carleen R. Spitzer, Min-Ae Song, Srabani Mitra, Anasuya Sarkar, Peter G. Shields, Philip T. Diaz, Mark D. Wewers
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Inflammasomes
THP-1 Cells
animal diseases
Bronchoalveolar Lavage
Plasma
0302 clinical medicine
Immunology and Allergy
Original Research
medicine.diagnostic_test
Chemistry
Inflammasome
hemic and immune systems
respiratory system
3. Good health
Respiratory Function Tests
Up-Regulation
medicine.anatomical_structure
Cellular Microenvironment
Female
medicine.symptom
medicine.drug
lcsh:Immunologic diseases. Allergy
Adult
endocrine system
Immunology
Inflammation
Context (language use)
ASC
smoking
lung
Cigarette Smoking
03 medical and health sciences
Zymogen
medicine
Extracellular
pneumonia
Humans
Lung
Macrophages
HIV
medicine.disease
respiratory tract diseases
CARD Signaling Adaptor Proteins
Pneumonia
030104 developmental biology
Bronchoalveolar lavage
Protein Multimerization
lcsh:RC581-607
030215 immunology
Zdroj: Frontiers in Immunology
Frontiers in Immunology, Vol 11 (2020)
ISSN: 1664-3224
DOI: 10.3389/fimmu.2020.00461
Popis: Rationale: Caspase-1 is a zymogen whose activation predominantly depends upon the assembly of ASC monomers into insoluble prion-like polymers (specks). ASC polymers support caspase-1 dimer formation inducing a proximity mediated auto-activation of caspase-1. Therefore, the amount and nature of ASC monomers and polymers in lung bronchoalveolar lavage fluid (BALF) might serve as a marker of lung inflammasome activity. Objectives: To determine whether lung ASC concentrations or oligomerization status predicts lung function or activity of lung inflammation. Methods: BALF ASC amount and oligomerization status was studied in three distinct cohorts: (1) young healthy non-smokers, vapers and smokers; (2) healthy HIV+ smokers who underwent detailed lung function studies; and (3) hospitalized patients with suspected pneumonia. We quantified cell free BALF ASC levels by ELISA and immunoblot. Oligomers (i.e., ASC specks) were identified by chemical crosslinking and ability to sediment with centrifugation. Measurement and Main Results: ASC levels are significantly higher in lung lining fluid than in plasma as well as higher in smoker lungs compared to non-smoker lungs. In this context, ASC levels correlate with macrophage numbers, smoking intensity and loss of lung diffusion capacity in a well-characterized cohort of healthy HIV+ smokers. However, only monomeric ASC was found in our BALF samples from all subjects, including patients with lung infections. Conclusions: Even though, most, if not all, extracellular ASC in BALF exists in the soluble, monomeric form, monomeric ASC concentrations still reflect the inflammatory status of the lung microenvironment and correlate with loss of lung function.
Databáze: OpenAIRE
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