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CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma
Marc Gauthier1, Sagar Laxman Kale1, Timothy B Oriss1
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
The Journal of Allergy and Clinical Immunology
|March 9, 2023
Summary
Chemokine CCL5 drives type 1 (T1) inflammation in asthma, particularly in tissue-resident memory T-cells (TRMs). Paradoxically, CCL5 also correlates with type 2 (T2) inflammation and eosinophilia, complicating its role.
Area of Science:
- Immunology
- Pulmonology
- Allergy and Asthma Research
Background:
- Type 1 (T1) inflammation, characterized by interferon-gamma (IFN-γ) expression, is increasingly recognized in asthma subsets.
- The specific contribution of T1 inflammation to asthma pathogenesis remains incompletely understood.
Purpose of the Study:
- To elucidate the role of chemokine ligand 5 (CCL5) in T1-driven asthma inflammation.
- To investigate the interplay between CCL5, T1 inflammation, and type 2 (T2) inflammation in asthma.
Main Methods:
- Analysis of CCL5, CXCL9, and CXCL10 messenger RNA (mRNA) expression in sputum from the Severe Asthma Research Program III (SARP III) cohort.
- Assessment of CCL5 and IFN-γ expression in bronchoalveolar lavage cells from the Immune Mechanisms in Severe Asthma (IMSA) cohort.
- Evaluation of CCL5's role in tissue-resident memory T-cell (TRM) reactivation using a T1-high murine severe asthma model.
Main Results:
- Sputum CCL5 expression strongly correlated with T1 chemokines (CXCL9, CXCL10), supporting its role in T1 inflammation.
- Elevated CCL5 levels were associated with increased fractional exhaled nitric oxide, blood and sputum eosinophils, and sputum neutrophils.
- Increased CCL5 in bronchoalveolar lavage fluid was specific to a T1-high/T2-variable/lymphocytic patient group, with IFN-γ trending with worsening lung obstruction in this subgroup.
- In a murine model, CCL5 receptor CCR5 was highly expressed on TRMs, and CCR5 inhibition blunted TRM reactivation.
Conclusions:
- CCL5 contributes to T1 neutrophilic inflammation mediated by TRMs in asthma.
- CCL5 exhibits a paradoxical association with T2 inflammation markers, including sputum eosinophilia.
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