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Journal of Allergy and Clinical Immunology

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CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma - 05/07/23

Doi : 10.1016/j.jaci.2023.02.028 
Marc Gauthier, MD a, ⁎ , Sagar Laxman Kale, PhD a, Timothy B. Oriss, PhD a, Michael Gorry, BS, MIS a, Richard P. Ramonell, MD a, Kathryn Dalton, BS a, Prabir Ray, PhD a, John V. Fahy, MD d, Max A. Seibold, PhD e, f, Mario Castro, MD, MPH g, Nizar Jarjour, MD h, Benjamin Gaston, MD i, Eugene R. Bleecker, MD j, Deborah A. Meyers, PhD j, Wendy Moore, MD k, Annette T. Hastie, PhD k, Elliot Israel, MD l, Bruce D. Levy, MD l, David Mauger, PhD m, Serpil Erzurum, MD n, Suzy A. Comhair, PhD n, Sally E. Wenzel, MD a, b, Anuradha Ray, PhD a, c
a Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa 
b Department of Environmental and Occupation Health, University of Pittsburgh School of Public Health, Pittsburgh, Pa 
c Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pa 
d Division of Pulmonary Allergy and Critical Care, University of California, San Francisco, Calif 
e Center for Genes, Environment, and Health and Department of Pediatrics, National Jewish Health, Denver, Colo 
f Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado—Anschutz Medical Campus, Aurora, Colo 
g Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, Kan 
h Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, Wis 
i Riley Hospital for Children and Indiana University School of Medicine Department of Pediatrics, Indianapolis, Ind 
j Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz 
k Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 
l Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass 
m Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, Pa 
n Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio 

∗Corresponding author: Marc Gauthier, MD, UPMC Montefiore 628NW, 3459 Fifth Ave, Pittsburgh, PA 15213.UPMC Montefiore 628NW3459 Fifth AvePittsburghPA15213

Abstract

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.

Le texte complet de cet article est disponible en PDF.

Key words : Asthma, IFN-γ, CXCL-10, CXCL9, CCL5, CCR5, maraviroc, tissue-resident memory T cells (TRM)

Abbreviations used : AHR, BAL, BMI, CCL5, CCR5, CXCL10, CXCL9, CXCR3, Cyclic-di-GMP, CyTOF, Feno, FVC, FVD, HDM, IMSA, IQR, MMA, RNA-Seq, SA, SARP, T1/2, TRM


Plan


 The first 2 authors contributed equally to this article, and both should be considered first author.
 Supported by the National Institutes of Health (AI106684 to A.R. and S.E.W.; F32 HL137089 to M.G.; HL113956 to A.R.; and AI048927 to A.R.), UPMC Competitive Medical Research Fund (M.G.), and the Parker B. Francis Foundation (M.G.). The following companies provided financial support for the Severe Asthma Research Program (SARP) study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and TEVA. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.
 Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.


© 2023  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 152 - N° 1

P. 94 - juillet 2023 Retour au numéro
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