CSF3R/CD114 mediates infection-dependent transition to severe asthma

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Presentation transcript:

CSF3R/CD114 mediates infection-dependent transition to severe asthma Hao Wang, PhD, Meaghan FitzPatrick, PhD, Nicholas J. Wilson, PhD, Desiree Anthony, PhD, Patrick C. Reading, PhD, Catherine Satzke, PhD, Eileen M. Dunne, PhD, Paul V. Licciardi, PhD, Huei Jiunn Seow, BSc Hons, Kristy Nichol, PhD, Ian M. Adcock, PhD, Kian Fan Chung, MD, DSc, Gary P. Anderson, PhD, Ross Vlahos, PhD, Peter Wark, MD, PhD, Steven Bozinovski, PhD Journal of Allergy and Clinical Immunology Volume 143, Issue 2, Pages 785-788.e6 (February 2019) DOI: 10.1016/j.jaci.2018.10.001 Copyright © 2018 The Authors Terms and Conditions

Fig 1 CSF3 expression is increased in those with poorly controlled asthma. (A) CSF3 and (B) CSF3R gene expression in bronchial biopsies was analyzed by RT-quantitative PCR from subjects with asthma (n = 26) grouped according to their inflammatory phenotype (non-NA vs NA). C, The percentages of neutrophils from matching BAL samples were compared with CSF3 expression. CSF3 expression levels were presented according to (D) atopy status and (E) bacterial culture status. F, In addition, CSF3 was compared with Muc5AC expression. NEG, Negative; POS, positive. Analysis includes nonparametric Mann-Whitney T test and Spearman correlation, and data are expressed as median ± interquartile range. Journal of Allergy and Clinical Immunology 2019 143, 785-788.e6DOI: (10.1016/j.jaci.2018.10.001) Copyright © 2018 The Authors Terms and Conditions

Fig 2 Neutralizing CSF3R reduced mucus production and airway hyperreactivity. (A) BAL neutrophil numbers, (B) neutrophil elastase (NE) activity, and (C) dsDNA levels were measured in control (SAL) and coinfected/HDM-exposed mice (CO-HDM) treated with anti-CSF3R or isotype (ISO) control antibody. (D) Single-cell suspensions from homogenized lungs were analyzed by flow cytometry where neutrophils were gated (Siglec F−, Ly6G+) and (E) presented as a percentage of the total CD45+ cells. F, Peroxidase activity from lung tissue was determined and presented as a percentage of the SAL control group. (G) Mucus was stained by Alcian blue-periodic acid Schiff (AB-PAS) and quantified (H) as detailed in the Methods section. I, Newtonian resistance (Rn, central airway resistance) was measured in vivo using Flexivent. dsDNA, Double-stranded DNA; SAL, saline alone. Data are expressed as mean ± SEM. n = 6-10 per group, *P < .05, 1-way ANOVA with Tukey post hoc test compared with CO-HDM/ISO. Journal of Allergy and Clinical Immunology 2019 143, 785-788.e6DOI: (10.1016/j.jaci.2018.10.001) Copyright © 2018 The Authors Terms and Conditions

Fig E1 Neonatal coinfection and HDM challenge promotes lung infection and mucus. Twenty-four hours after final HDM challenge (age 40-42 days), S pneumoniae load in the (A) nasopharynx and (B) lung tissue was determined. (C) AB-PAS was used to stain airway mucus (purple) (D) and was quantified as detailed in the Methods section. E, Expression of the mucin gene Muc5AC in lung tissue was analyzed by RT-quantitative PCR. (F) Eosinophil and (G) neutrophils BAL numbers are presented across treatment groups, and (Fig E1, F) RT-quantitative PCR was performed on lung tissue for assessment of CSF3 using GAPDH as a reference gene. n = 4-8 per group. #P < .05, 2-way ANOVA analysis with Tukey post hoc test compared with SP/HDM. AB-PAS, Alcian blue-periodic acid Schiff; CFU, colony forming unit; GAPDH, glyceraldehyde phosphate dehydrogenase; IAV, influenza A virus; SP, Streptococcus pneumoniae. Data are expressed as median ± interquartile range in Fig E1 (A and B) or mean ± SEM in Fig E1 (D to H). Journal of Allergy and Clinical Immunology 2019 143, 785-788.e6DOI: (10.1016/j.jaci.2018.10.001) Copyright © 2018 The Authors Terms and Conditions

Fig E2 Neutralizing CSF3R did not affect pneumococcal nasal or lung load. A, In the last week of HDM challenge, mice were treated with 100 μg anti-CSF3R antibody (α-CSF3R) or isotype control antibody (ISO) by intraperitoneal injection every second day. Twenty-four hours after final HDM/antibody administration, S pneumoniae load in the (B) nasopharynx, (C) BAL fluid, and (D) lung tissue was determined (n = 9-10 per group). IAV, Influenza A virus; CFU, colony forming unit; PFU, plaque forming unit; SP, Streptococcus pneumoniae. Data are expressed as median ± interquartile range. Journal of Allergy and Clinical Immunology 2019 143, 785-788.e6DOI: (10.1016/j.jaci.2018.10.001) Copyright © 2018 The Authors Terms and Conditions

Fig E3 CSF3 and CSF3R expression in the U-BIOPRED cohort. Baseline transcript expression of (A) CSF3 and (B) CSF3R in sputum cells analyzed by microarray profiling of those with severe asthma (nonsmokers) and healthy controls enrolled within the U-BIOPRED cohort. ES, Enrichment Score. Journal of Allergy and Clinical Immunology 2019 143, 785-788.e6DOI: (10.1016/j.jaci.2018.10.001) Copyright © 2018 The Authors Terms and Conditions