UGRP1-modulated MARCO+ alveolar macrophages contribute to age-related lung fibrosis

Yongyan Chen; Xiaolei Hao; Ming Li; Zhigang Tian; Min Cheng

doi:10.1186/s12979-023-00338-8

UGRP1-modulated MARCO⁺ alveolar macrophages contribute to age-related lung fibrosis

Immun Ageing. 2023 Mar 18;20(1):14. doi: 10.1186/s12979-023-00338-8.

Authors

Yongyan Chen^{1

2}, Xiaolei Hao^{3

4}, Ming Li⁵, Zhigang Tian^{3

4

6}, Min Cheng^{7

8

9

10}

Affiliations

¹ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. yychen08@ustc.edu.cn.
² Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China. yychen08@ustc.edu.cn.
³ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
⁴ Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China.
⁵ Department of Pathology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China.
⁶ Cancer Immunotherapy Center, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, 230001, China.
⁷ Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China. chengmin@ustc.edu.cn.
⁸ Cancer Immunotherapy Center, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, 230001, China. chengmin@ustc.edu.cn.
⁹ Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China. chengmin@ustc.edu.cn.
¹⁰ Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, 230001, China. chengmin@ustc.edu.cn.

Abstract

The aging lungs are vulnerable to chronic pulmonary diseases; however, the underlying mechanisms are not well understood. In this study, we compared the aging lungs of 20-24-month-old mice with the young of 10-16-week-old mice, and found that aging airway epithelial cells significantly upregulated the expression of uteroglobin-related protein 1 (UGRP1), which was responsible for the higher levels of CCL6 in the aging lungs. Alveolar macrophages (AMs) changed intrinsically with aging, exhibiting a decrease in cell number and altered gene expression. Using terminal differentiation trajectories, a population of MARCO⁺ AMs with the ability to produce CCL6 was identified in the aging lungs. Upregulated UGRP1was demonstrated to modulate CCL6 production of AMs in the UGRP1-MARCO pair in vivo and in vitro. Furthermore, MARCO⁺ AMs aggravated bleomycin-induced pulmonary fibrosis in a CCL6-dependent manner in the aged mice, and blocking MARCO or neutralizing CCL6 significantly inhibited pulmonary fibrosis, similar to the depletion of AMs. The age-related upregulation of UGRP1 and MARCO⁺ AMs, involved in the progression of lung fibrosis, was also observed in human lung tissues. Thus, UGRP1 modulated MARCO⁺ AMs regarding the age-related lung fibrosis in a CCL6-dependent manner, which is key to establishing optimal targeting for the aging population.

Keywords: Age-related lung fibrosis; Alveolar macrophage; CCL6; MARCO; UGRP1.

Abstract

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