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Dynamically upregulated mast cell CPA3 patterns in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

Siddhuraj, Premkumar LU ; Jönsson, Jimmie ; Alyamani, Manar LU ; Prabhala, Pavan LU ; Magnusson, Mattias LU ; Lindstedt, Sandra LU and Erjefält, Jonas S. LU (2022) In Frontiers in Immunology 13.
Abstract

Background: The mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cell CPA3 expression in lung diseases remain unknown. Methods: Using a histology-based approach for quantitative spatial decoding of mRNA and protein single cell, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from control subjects and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF). Results: Mast cells in COPD lungs had an anatomically widespread increase of CPA3 mRNA (bronchioles p < 0.001, pulmonary vessels p < 0.01, and alveolar parenchyma... (More)

Background: The mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cell CPA3 expression in lung diseases remain unknown. Methods: Using a histology-based approach for quantitative spatial decoding of mRNA and protein single cell, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from control subjects and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF). Results: Mast cells in COPD lungs had an anatomically widespread increase of CPA3 mRNA (bronchioles p < 0.001, pulmonary vessels p < 0.01, and alveolar parenchyma p < 0.01) compared to controls, while granule-stored CPA3 protein was unaltered. IPF lungs had a significant upregulation of both mast cell density, CPA3 mRNA (p < 0.001) and protein (p < 0.05), in the fibrotic alveolar tissue. Spatial expression maps revealed altered mast cell mRNA/protein quotients in lung areas subjected to disease-relevant histopathological alterations. Elevated CPA3 mRNA also correlated to lung tissue eosinophils, CD3 T cells, and declined lung function. Single-cell RNA sequencing of bronchial mast cells confirmed CPA3 as a top expressed gene with potential links to both inflammatory and protective markers. Conclusion: This study shows that lung tissue mast cell populations in COPD and IPF lungs have spatially complex and markedly upregulated CPA3 expression profiles that correlate with immunopathological alterations and lung function. Given the proposed roles of CPA3 in tissue homeostasis, remodeling, and inflammation, these alterations are likely to have clinical consequences.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
carboxypeptidase A3, COPD, lung, mast cells, tryptase
in
Frontiers in Immunology
volume
13
article number
924244
publisher
Frontiers Media S. A.
external identifiers
  • pmid:35983043
  • scopus:85136125470
ISSN
1664-3224
DOI
10.3389/fimmu.2022.924244
language
English
LU publication?
yes
id
d2b74995-6f41-4674-9974-2f8122ce7cdc
date added to LUP
2022-10-18 15:48:27
date last changed
2024-07-11 16:40:56
@article{d2b74995-6f41-4674-9974-2f8122ce7cdc,
  abstract     = {{<p>Background: The mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cell CPA3 expression in lung diseases remain unknown. Methods: Using a histology-based approach for quantitative spatial decoding of mRNA and protein single cell, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from control subjects and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF). Results: Mast cells in COPD lungs had an anatomically widespread increase of CPA3 mRNA (bronchioles p &lt; 0.001, pulmonary vessels p &lt; 0.01, and alveolar parenchyma p &lt; 0.01) compared to controls, while granule-stored CPA3 protein was unaltered. IPF lungs had a significant upregulation of both mast cell density, CPA3 mRNA (p &lt; 0.001) and protein (p &lt; 0.05), in the fibrotic alveolar tissue. Spatial expression maps revealed altered mast cell mRNA/protein quotients in lung areas subjected to disease-relevant histopathological alterations. Elevated CPA3 mRNA also correlated to lung tissue eosinophils, CD3 T cells, and declined lung function. Single-cell RNA sequencing of bronchial mast cells confirmed CPA3 as a top expressed gene with potential links to both inflammatory and protective markers. Conclusion: This study shows that lung tissue mast cell populations in COPD and IPF lungs have spatially complex and markedly upregulated CPA3 expression profiles that correlate with immunopathological alterations and lung function. Given the proposed roles of CPA3 in tissue homeostasis, remodeling, and inflammation, these alterations are likely to have clinical consequences.</p>}},
  author       = {{Siddhuraj, Premkumar and Jönsson, Jimmie and Alyamani, Manar and Prabhala, Pavan and Magnusson, Mattias and Lindstedt, Sandra and Erjefält, Jonas S.}},
  issn         = {{1664-3224}},
  keywords     = {{carboxypeptidase A3; COPD; lung; mast cells; tryptase}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Dynamically upregulated mast cell CPA3 patterns in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2022.924244}},
  doi          = {{10.3389/fimmu.2022.924244}},
  volume       = {{13}},
  year         = {{2022}},
}