Blocking CD226 regulates ILC2 effector function and alleviates airway hyperreactivity.

Jan 22, 2024

Experts: Yoshihiro Sakano,Kei Sakano,Benjamin P Hurrell,Doumet Georges Helou,Pedram Shafiei-Jahani,Mohammad H Kazemi,Xin Li,Stephen Shen,James R Hilser,Jaana A Hartiala,Hooman Allayee,Richard Barbers,Omid Akbari

Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases.
We aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR).
We administered IL-33 intranasally to wild-type mice, followed by treatment with anti-CD226 antibody or isotype control. Pulmonary ILC2s were sorted for ex vivo analyses through RNA sequencing and flow cytometry. Next, we evaluated the effects of CD226 on AHR and lung inflammation in wild-type and Rag2 mice. Additionally, we compared peripheral ILC2s from healthy donors and asthmatic patients to ascertain the role of CD226 in human ILC2s.
Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Mechanistically, CD226 alters intracellular metabolism and enhances PI3K/AKT and MAPK signal pathways. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria Alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls.
Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.

Copyright © 2024. Published by Elsevier Inc.

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ABOUT THE EXPERTS

Yoshihiro Sakano,Kei Sakano,Benjamin P Hurrell,Doumet Georges Helou,Pedram Shafiei-Jahani,Mohammad H Kazemi,Xin Li,Stephen Shen,James R Hilser,Jaana A Hartiala,Hooman Allayee,Richard Barbers,Omid Akbari

Yoshihiro Sakano

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Kei Sakano

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Benjamin P Hurrell

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Doumet Georges Helou

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Pedram Shafiei-Jahani

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Mohammad H Kazemi

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Xin Li

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Stephen Shen

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

James R Hilser

Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine University of Southern California, Los Angeles, CA, USA.

Jaana A Hartiala

Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine University of Southern California, Los Angeles, CA, USA.

Hooman Allayee

Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine University of Southern California, Los Angeles, CA, USA.

Richard Barbers

Department of Clinical Medicine, Division of Pulmonary and Critical Care Medicine, Keck School of Medicine of USC, University of Southern California Hospital, Los Angeles, CA, USA.

Omid Akbari

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: akbari@usc.edu.