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Theranostics 2024; 14(1):159-175. doi:10.7150/thno.88678 This issue Cite

Research Paper

LCP1 knockdown in monocyte-derived macrophages: mitigating ischemic brain injury and shaping immune cell signaling and metabolism

Yan Wang^1,2#✉, Qianqian Yin^1#, Decao Yang¹, Haojie Jin³, Yang Yao², Jibing Song⁴, Cuiying Liu⁵, Yu Nie⁶, Hao Yin⁷, Wei Wang^8,9, Baohui Xu¹⁰, Lixiang Xue¹, Xunming Ji¹¹, Xiaoyuan Chen^12✉, Heng Zhao^11✉

1. Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
2. Department of Neurosurgery, Stanford University School of Medicine, 1201 Welch Road, MSLS Building, Stanford, USA.
3. The Key Laboratory for Silviculture and Conservation of Ministry of Education, The College of forestry, Beijing Forestry University, Beijing, China.
4. College of Chemistry, Beijing University of Chemical Technology, China.
5. School of Nursing, Capital Medical University, Beijing, China.
6. Fuwai Hospital, National Centre for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China.
7. Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai, China.
8. Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
9. Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China.
10. Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, MSLS Building, Stanford, USA.
11. Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China.
12. Department of Diagnostic Radiology, Nanomedicine Translational Research Program, NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
# These authors contributed equally

✉ Corresponding author: Yan Wang, PhD, E-mail: yanwang2019edu.cn. Xiaoyuan Chen, PhD, E-mail: chen.shawnedu.sg. Heng Zhao, PhD, E-mail: heng.zhao10com.

Abstract

Rationale: Ischemic stroke poses a significant health burden with limited treatment options. Lymphocyte Cytosolic Protein 1 (LCP1) facilitates cell migration and immune responses by aiding in actin polymerization, cytoskeletal rearrangements, and phagocytosis. We have demonstrated that the long non-coding RNA (lncRNA) Maclpil silencing in monocyte-derived macrophages (MoDMs) led to LCP1 inhibition, reducing ischemic brain damage. However, the role of LCP1 of MoDMs in ischemic stroke remains unknown.

Methods and Results: We investigated the impact of LCP1 on ischemic brain injury and immune cell signaling and metabolism. We found that knockdown of LCP1 in MoDMs demonstrated robust protection against ischemic infarction and improved neurological behaviors in mice. Utilizing the high-dimensional CyTOF technique, we demonstrated that knocking down LCP1 in MoDMs led to a reduction in neuroinflammation and attenuation of lymphopenia, which is linked to immunodepression. It also showed altered immune cell signaling by modulating the phosphorylation levels of key kinases and transcription factors, including p-PLCg2, p-ERK1/2, p-EGFR, p-AKT, and p4E-BP1 as well as transcription factors like p-STAT1, p-STAT3, and p-STAT4. Further bioinformatic analysis indicated that Akt and EGFR are particularly involved in fatty acid metabolism and glycolysis. Indeed, single-cell sequencing analysis confirmed that enrichment of fatty acid and glycolysis metabolism in Lcp1^high monocytes/macrophages. Furthermore, Lcp1^high cells exhibited enhanced oxidative phosphorylation, chemotaxis, migration, and ATP biosynthesis pathways. In vitro experiments confirmed the role of LCP1 in regulating mitochondrial function and fatty acid uptake.

Conclusions: These findings contribute to a deeper understanding of LCP1 in the context of ischemic stroke and provide valuable insights into potential therapeutic strategies targeting LCP1 and metabolic pathways, aiming to attenuating neuroinflammation and lymphopenia.

Keywords: Stroke, Monocytes, Macrophages, Lipid Metabolism, Neuroinflammation, Immunodepression

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