Macrophage‐derived progranulin promotes allergen‐induced airway inflammation

• Published in: Allergy (Copenhagen) Vol. 75; no. 5; pp. 1133 - 1145
• Main Authors: Choi, Jun‐Pyo, Park, So Young, Moon, Keun‐Ai, Ha, Eun Hee, Woo, Yeon Duk, Chung, Doo Hyun, Kwon, Hyouk‐Soo, Kim, Tae‐Bum, Park, Hae‐Sim, Moon, Hee‐Bom, Song, Woo‐Jung, Cho, You Sook
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01-05-2020
• Subjects: airway; Allergens; Allergies; Alveoli; Animal models; Animals; Asthma; Bronchus; Cell lines; Cytokines; Disease Models, Animal; Epithelial cells; house dust mite; Hypersensitivity; Hypersensitivity - immunology; Immune response; Inflammation; Inflammatory diseases; Lymphocytes T; macrophage; Macrophages; Mice; Natural killer cells; progranulin; Progranulins; Pyroglyphidae; Respiratory tract; Respiratory tract diseases; Rodents; Th2 Cells; Thymic stromal lymphopoietin; progranulin; macrophage; house dust mite; inflammation; airway
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.14129

Background
Progranulin (PGRN), mainly produced by immune and epithelial cells, has been known to be involved in the development of various inflammatory diseases. However, the function of PGRN in allergic airway inflammation has not been clearly elucidated, and we investigated the role of PGRN in allergic airway inflammation.
Methods
Production of PGRN and various type 2 cytokines was evaluated in mouse airways exposed to house dust mite allergen, and main cellular sources of these molecules were investigated using macrophage, airway epithelial cell, and NKT cell lines. We elucidated the role of PGRN in allergic airway inflammation in mouse models of asthma using macrophage‐derived PGRN‐deficient mice and NKT cell knockout mice by evaluating cytokine levels in bronchoalveolar lavage fluids and histopathology. We also supplemented recombinant PGRN in the mouse models to confirm the role of PGRN in allergic airway inflammation.
Results
PGRN production preceded other cytokines, mainly from macrophages, in the airway exposed to allergen. PGRN induced IL‐4 and IL‐13 production in NKT cells and IL‐33 and TSLP in airway epithelial cells. PGRN‐induced Th2 cytokine production was abolished in NKT‐deficient mice. Finally, allergic inflammation was significantly attenuated in allergen‐exposed PGRN‐deficient mice, but inflammation was restored when recombinant PGRN was supplemented during the allergen sensitization period.
Conclusion
The presence of macrophage‐derived PGRN in airways in the early sensitization period may be critical for mounting a Th2 immune response and for following an allergic airway inflammation pathway via induction of type 2 cytokine production in NKT and airway epithelial cells.
During allergen sensitization, PGRN, produced mainly from alveolar macrophages, induces type 2 cytokines (IL‐4, IL‐13, IL‐33, and TSLP) via NKT cells and lung epithelial cells. The absence of alveolar macrophage‐derived PGRN or NKT cells in sensitization period induces downregulation of type 2 cytokines and development of allergen‐specific Th2 airway inflammation. Abbreviations: PGRN, progranulin; TSLP, thymic stromal lymphopoietin