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Inflammasome Genetic Variants, Macrophage Function, and Clinical Outcomes in Cystic Fibrosis.
Graustein, AD, Berrington, WR, Buckingham, KJ, Nguyen, FK, Joudeh, LL, Rosenfeld, M, Bamshad, MJ, Gibson, RL, Hawn, TR, Emond, MJ
American journal of respiratory cell and molecular biology. 2021;(2):157-166
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Abstract
Cystic fibrosis (CF) is characterized by chronic airway infection, inflammation, and tissue damage that lead to progressive respiratory failure. NLRP3 and NLRC4 are cytoplasmic pattern recognition receptors that activate the inflammasome, initiating a caspase-1-mediated response. We hypothesized that gain-of-function inflammasome responses are associated with worse outcomes in children with CF. We genotyped nonsynonymous variants in NLRP3 and the NLRC4 pathway from individuals in the EPIC (Early Pseudomonas Infection Control) Observational Study cohort and tested for association with CF outcomes. We generated knockouts of NLRP3 and NLRC4 in human macrophage-like cells and rescued knockouts with wild-type or variant forms of NLRP3 and NLRC4. We identified a SNP in NLRP3, p.(Q705K), that was associated with a higher rate of P. aeruginosa colonization (N = 609; P = 0.01; hazard ratio, 2.3 [Cox model]) and worsened lung function over time as measured by forced expiratory volume in 1 second (N = 445; P = 0.001 [generalized estimating equation]). We identified a SNP in NLRC4, p.(A929S), that was associated with a lower rate of P. aeruginosa colonization as part of a composite of rare variants (N = 405; P = 0.045; hazard ratio, 0.68 [Cox model]) and that was individually associated with protection from lung function decline (P < 0.001 [generalized estimating equation]). Rescue of the NLRP3 knockout with the p.(Q705K) variant produced significantly more IL-1β in response to NLRP3 stimulation than rescue with the wild type (P = 0.020 [Student's t test]). We identified a subset of children with CF at higher risk of early lung disease progression. Knowledge of these genetic modifiers could guide therapies targeting inflammasome pathways.
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Impaired Cholesterol-Uptake Capacity of HDL Might Promote Target-Lesion Revascularization by Inducing Neoatherosclerosis After Stent Implantation.
Nagano, Y, Otake, H, Toba, T, Kuroda, K, Shinkura, Y, Tahara, N, Tsukiyama, Y, Yanaka, K, Yamamoto, H, Nagasawa, A, et al
Journal of the American Heart Association. 2019;(9):e011975
Abstract
Background We evaluated the importance of high-density lipoprotein (HDL) functionality for target-lesion revascularization in patients treated with coronary stents using a rapid cell-free assay system to evaluate the functional capacity of HDL to accept additional cholesterol (cholesterol-uptake capacity; CUC). Methods and Results From an optical coherence tomography (OCT) registry of patients treated with coronary stents, 207 patients were enrolled and their HDL was functionally evaluated by measuring the CUC. Follow-up OCT was performed (median duration, 24.5 months after stenting) to evaluate the presence of neoatherosclerosis. Clinical follow-up was performed to assess target-lesion revascularization for a median duration of 42.3 months after stent implantation. Neoatherosclerosis was identified in 37 patients (17.9%). Multivariate logistic regression analysis revealed that a decreased CUC was independently associated with neoatherosclerosis (odds ratio, 0.799; P<0.001). The CUC showed a significant inverse correlation with incidence of target-lesion revascularization (odds ratio, 0.887; P=0.003) and with lipid accumulation inside stents, suggesting that neoatherosclerosis contributes to the association between CUC and target-lesion revascularization. Conclusions Impaired HDL functionality, detected as decreased CUC, might lead to future stent failure by provoking atherogenic changes of the neointima within stents. Both quantitative and qualitative assessments of HDL might enable the improved prediction of clinical outcomes after stent implantation.
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Aging-related effects of bed rest followed by eccentric exercise rehabilitation on skeletal muscle macrophages and insulin sensitivity.
Reidy, PT, Lindsay, CC, McKenzie, AI, Fry, CS, Supiano, MA, Marcus, RL, LaStayo, PC, Drummond, MJ
Experimental gerontology. 2018;:37-49
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Abstract
The pro- and anti-inflammatory macrophages are associated with insulin sensitivity and skeletal muscle regeneration. Infiltrating macrophages in skeletal muscle during a period of physical inactivity and subsequent reloading/rehabilitation in older adults is unknown, but may provide insight into mechanisms related to the development of metabolic disease and changes in muscle cell size. The purpose of this study was to determine if skeletal muscle macrophage infiltration is modulated differently between young and older adults after bed rest and exercise rehabilitation and if these responses are related to muscle and insulin sensitivity changes. 14 young and 9 older adults underwent 5-days of bed rest followed by 8-weeks of lower limb eccentric exercise rehabilitation (REHAB). Dual-energy X-ray absorptiometry, magnetic resonance imaging and myofiber analysis were used to identify muscle morphology and CLIX-IR and CLIX-β were used to assess insulin sensitivity. Skeletal muscle macrophages, CD68 (pan), CD11b (M1), CD163 (M2), CD206 (M2), were characterized using immunohistochemistry and gene expression. Insulin sensitivity, independent of age, decreased ~38% following bed rest and was restored following REHAB. We found robust age-related differences in muscle atrophy during bed rest, yet older and younger adults equally hypertrophied during REHAB. Interestingly, there were age-related differences in macrophage content (CD68+CD11b+ and CD68+CD11b- cells) but both young and old similarly increased macrophages with REHAB. Satellite cell changes during rehab corresponded to macrophage content changes. Muscle tissue resident macrophages and gene expression, were not associated with changes in insulin sensitivity following bed rest and REHAB. These data suggest that muscle macrophages are modulated as a result of exercise rehabilitation following bed rest and may more associated with muscle regrowth/hypertrophy rather than insulin sensitivity in young or older adults. This trial was registered at clinicaltrials.gov as NCT01669590.
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Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals.
Zanni, MV, Toribio, M, Wilks, MQ, Lu, MT, Burdo, TH, Walker, J, Autissier, P, Foldyna, B, Stone, L, Martin, A, et al
The Journal of infectious diseases. 2017;(8):1264-1269
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Abstract
BACKGROUND The ability to noninvasively assess arterial CD206+ macrophages may lead to improved understanding of human immunodeficiency virus (HIV)-associated cardiovascular disease. METHODS We trialed a novel macrophage-specific arterial imaging technique. RESULTS We demonstrated colocalization between technetium Tc 99m tilmanocept (99mTc-tilmanocept) and CD206+ macrophages ex vivo. In vivo application of 99mTc-tilmanocept single-photon emission computed tomography/computed tomography revealed high-level 99mTc-tilmanocept uptake across 20.4% of the aortic surface volume among HIV-infected subjects, compared with 4.3% among non-HIV-infected subjects (P = .009). Among all subjects, aortic high-level 99mTc-tilmanocept uptake was related to noncalcified aortic plaque volume (r = 0.87; P = .003) on computed tomographic angiography, and this relationship held when we controlled for HIV status. CONCLUSION These first-in-human data introduce a novel macrophage-specific arterial imaging technique in HIV. CLINICAL TRIALS REGISTRATION NCT02542371.