Browsing by Author "Mauger, David"

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    CCL5 is a Potential Bridge Between Type-1 and Type-2 Inflammation in Asthma
    (Elsevier, 2023) Gauthier, Marc; Kale, Sagar Laxman; Oriss, Timothy B.; Gorry, Michael; Ramonell, Richard P.; Dalton, Kathryn; Ray, Prabir; Fahy, John V.; Seibold, Max A.; Castro, Mario; Jarjour, Nizar; Gaston, Benjamin; Bleecker, Eugene R.; Meyers, Deborah A.; Moore, Wendy; Hastie, Annette T.; Israel, Elliot; Levy, Bruce D.; Mauger, David; Erzurum, Serpil; Comhair, Suzy A.; Wenzel, Sally E.; Ray, Anuradha; Pediatrics, School of Medicine
    Background: Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation. Methods: CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model. Results: Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation. Conclusion: CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.
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    Climatic and geographic predictors of life history variation in Eastern Massasauga (Sistrurus catenatus): A range-wide synthesis
    (Plos, 2017-02-14) Hileman, Eric T.; King, Richard B.; Adamski, John M.; Anton, Thomas G.; Bailey, Robyn L.; Baker, Sarah J.; Bieser, Nickolas D.; Bell Jr., Thomas A.; Bissell, Kristin M.; Bradke, Danielle R.; Campa III, Henry; Casper, Gary S.; Cedar, Karen; Cross, Matthew D.; DeGregorio, Brett A.; Dreslik, Michael J.; Faust, Lisa J.; Harvey, Daniel S.; Hay, Robert W.; Jellen, Benjamin C.; Johnson, Brent D.; Johnson, Glenn; Kiel, Brooke D.; Kingsbury, Bruce A.; Kowalski, Matthew J.; Lee, Yu Man; Lentini, Andrew M.; Marshall, John C.; Mauger, David; Moore, Jennifer A.; Paloski, Rori A.; Phillips, Christopher A.; Pratt, Paul D.; Preney, Thomas; Prior, Kent A.; Promaine, Andrew; Redmer, Michael; Reinert, Howard K.; Rouse, Jeremy D.; Shoemaker, Kevin T.; Sutton, Scott; VanDeWalle, Terry J.; Weatherhead, Patrick J.; Wynn, Doug; Yagi, Anne; Department of Biology, School of Science
    Elucidating how life history traits vary geographically is important to understanding variation in population dynamics. Because many aspects of ectotherm life history are climate-dependent, geographic variation in climate is expected to have a large impact on population dynamics through effects on annual survival, body size, growth rate, age at first reproduction, size-fecundity relationship, and reproductive frequency. The Eastern Massasauga (Sistrurus catenatus) is a small, imperiled North American rattlesnake with a distribution centered on the Great Lakes region, where lake effects strongly influence local conditions. To address Eastern Massasauga life history data gaps, we compiled data from 47 study sites representing 38 counties across the range. We used multimodel inference and general linear models with geographic coordinates and annual climate normals as explanatory variables to clarify patterns of variation in life history traits. We found strong evidence for geographic variation in six of nine life history variables. Adult female snout-vent length and neonate mass increased with increasing mean annual precipitation. Litter size decreased with increasing mean temperature, and the size-fecundity relationship and growth prior to first hibernation both increased with increasing latitude. The proportion of gravid females also increased with increasing latitude, but this relationship may be the result of geographically varying detection bias. Our results provide insights into ectotherm life history variation and fill critical data gaps, which will inform Eastern Massasauga conservation efforts by improving biological realism for models of population viability and climate change.
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    Clinical and molecular implications of RGS2 promoter genetic variation in severe asthma
    (Elsevier, 2022) Cardet, Juan Carlos; Kim, Donghwa; Bleecker, Eugene R.; Casale, Thomas B.; Israel, Elliot; Mauger, David; Meyers, Deborah A.; Ampleford, Elizabeth; Hawkins, Gregory A.; Tu, Yaping; Liggett, Stephen B.; Ortega, Victor E.; SARP-3 investigators; Pediatrics, School of Medicine
    Background: Regulator of G protein signaling (RGS) 2 terminates bronchoconstrictive Gαq signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outcomes is unknown. Objective: We sought to determine whether reductions in RGS2 expression seen with these 2 RGS2 promoter variants augment HASM contractility and associate with an asthma severity phenotype. Methods: We transfected HASM with a range of RGS2-specific small interfering RNA (siRNA) concentrations and determined RGS2 protein expression by Western blot analysis and intracellular calcium flux induced by histamine (a Gαq-coupled H1 receptor bronchoconstrictive agonist). We conducted regression-based genotype association analyses of RGS2 variants from 611 patients from the National Heart, Lung, and Blood Institute Severe Asthma Research Program 3. Results: RGS2-specific siRNA caused dose-dependent increases in histamine-stimulated bronchoconstrictive intracellular calcium signaling (2-way ANOVA, P < .0001) with a concomitant decrease in RGS2 protein expression. RGS2-specific siRNA did not affect Gαq-independent ionomycin-induced intracellular calcium signaling (P = .42). The minor allele frequency of rs2746071 and rs2746072 was 0.46 and 0.28 among African American/non-Hispanic Black patients and was 0.28 and 0.27 among non-Hispanic White patients, among whom these single nucleotide polymorphisms were in stronger linkage disequilibrium (r2 = 0.97). Among non-Hispanic White patients, risk allele homozygotes for rs2746072 and rs2746071 each had nearly 2-fold greater asthma exacerbation rates relative to alternative genotypes with wild-type alleles (Padditive = 2.86 × 10-5/Precessive = 5.22 × 10-6 and Padditive = 3.46 × 10-6/Precessive = 6.74 × 10-7, respectively) at baseline, which was confirmed by prospective longitudinal exacerbation data. Conclusion: RGS2 promoter variation associates with a molecular and clinical phenotype characterized by enhanced bronchoconstrictive stimulation in vitro and higher asthma exacerbations rates in non-Hispanic White patients.
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    Geography, generalisability, and susceptibility in clinical trials
    (Elsevier, 2021) Clougherty, Jane E.; Kinnee, Ellen J.; Cardet, Juan Carlos; Mauger, David; Bacharier, Leonard; Beigelman, Avraham; Blake, Kathryn V.; Cabana, Michael D.; Castro, Mario; Chmiel, James F.; Covar, Ronina; Fitzpatrick, Anne; Gaffin, Jonathan M.; Gentile, Deborah; Israel, Elliot; Jackson, Daniel J.; Kraft, Monica; Krishnan, Jerry A.; Kumar, Harsha Vardhan; Lang, Jason E.; Lazarus, Stephen C.; Lemanske, Robert F.; Lima, John; Martinez, Fernando D.; Morgan, Wayne; Moy, James; Myers, Ross; Naureckas, Edward T.; Ortega, Victor E.; Peters, Stephen P.; Phipatanakul, Wanda; Pongracic, Jacqueline A; Ross, Kristie; Sheehan, William J.; Smith, Lewis J.; Solway, Julian; Sorkness, Christine A.; Wechsler, Michael E.; Wenzel, Sally; White, Steven R.; Holguin, Fernando; Pediatrics, School of Medicine