LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia

Dong Wang; Xiaohui Li; Defeng Jiao; Ying Cai; Liting Qian; Yiqing Shen; Yichen Lu; Yonggang Zhou; Binqing Fu; Rui Sun; Zhigang Tian; Xiaohu Zheng; Haiming Wei

doi:10.1186/s13045-023-01429-1

LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia

J Hematol Oncol. 2023 Mar 27;16(1):30. doi: 10.1186/s13045-023-01429-1.

Authors

Dong Wang^#^{1

2

3}, Xiaohui Li^#^{2

3}, Defeng Jiao^{2

3}, Ying Cai⁴, Liting Qian⁴, Yiqing Shen^{2

3}, Yichen Lu^{2

3}, Yonggang Zhou^{2

3}, Binqing Fu^{2

3}, Rui Sun^{2

3}, Zhigang Tian^{2

3}, Xiaohu Zheng^{5

6

7}, Haiming Wei^{8

9

10}

Affiliations

¹ Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
² 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.
³ Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China.
⁴ The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, Anhui, China.
⁵ Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China. ustczxh@ustc.edu.cn.
⁶ 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. ustczxh@ustc.edu.cn.
⁷ Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China. ustczxh@ustc.edu.cn.
⁸ Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China. ustcwhm@ustc.edu.cn.
⁹ 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. ustcwhm@ustc.edu.cn.
¹⁰ Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China. ustcwhm@ustc.edu.cn.

^# Contributed equally.

Abstract

Background: Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins (e.g., interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome.

Methods: First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2, were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting.

Results: Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2, prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice.

Conclusions: Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.

Keywords: Cachexia; Ferroptosis; LCN2; Lung cancer; Neutrophils.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cachexia / etiology
Cachexia / metabolism
Cachexia / prevention & control
Ferroptosis*
Humans
Lipocalin-2
Lung Neoplasms* / complications
Mice
Muscles / metabolism
Neutrophils / metabolism

Substances

Lipocalin-2
LCN2 protein, human
Lcn2 protein, mouse