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Theranostics 2023; 13(6):2040-2056. doi:10.7150/thno.80555 This issue Cite

Research Paper

Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages

Xueqin Li^1*, Xin Chen^2*, Shengzhe Gong^1,3*, Jie Zhao¹, Chen Yao¹, Hanyong Zhu¹, Rui Xiao^1,3, Yongqin Qin^1,3, Rongqing Li¹, Na Sun¹, Xiangyang Li¹, Fuxing Dong⁴, Tingting Zhao^5✉, Yuchen Pan^1✉, Jing Yang^1✉

1. Jiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, The Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
2. Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
3. National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
4. Public Experimental Research Center, Xuzhou Medical University, Xuzhou, Jiangsu, China
5. Chongqing International Institute for Immunology, Chongqing, China
* These authors have contributed equally to this work.

✉ Corresponding authors: Jiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, The Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. Jing Yang, E-mail: jingyangedu.cn; Yuchen Pan, E-mail: panyuchenedu.cn. Chongqing International Institute for Immunology, No. 13 Tianchi Avenue, Banan District, Chongqing, China. Tingting Zhao, E-mail: zhaotingting95com More

Abstract

Rationale: Platelets can influence the progression and prognosis of colorectal cancer (CRC) through multiple mechanisms, including crosstalk with tumor-associated macrophages (TAMs). However, the mechanisms underlying the crosstalk between platelets and TAMs remain unclear. The present study aimed to investigate the role of intratumoral platelets in regulating the function of TAMs and to identify the underlying mechanisms.

Methods: The interaction of platelets with macrophages was assessed in the presence or absence of the indicated compounds in vivo. An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC mouse model was used to investigate the role of platelets in controlling CRC development. Multiplexed immunofluorescence staining, fluorescence-activated cell sorting (FACS), and RNA sequence analysis were used to examine the changes in TAMs. TAMs and bone marrow-derived macrophages (BMDMs) were treated with the indicated compounds or siRNA against specific targets, and the expression levels of signal transducer and activator of transcription 1 (STAT1), c-Jun N-terminal kinase (JNK), and P-selectin glycoprotein ligand-1 (PSGL-1) were measured by Western blotting. The mRNA expression levels of complement 5 (C5), complement 5a receptor 1 (C5ar1), Arginase 1 (Arg1) and Il10 were measured by real-time RT-PCR, and the complement 5a (C5a) concentration was measured by ELISA. The dual-luciferase reporter assay and ChIP assay were performed to examine the potential regulatory mechanisms of platelet induction of C5 transcription in TAMs.

Results: In our study, we found that an increase in platelets exacerbated CRC development, while inhibiting platelet adhesion attenuated tumor growth. Platelets signal TAMs through P-selectin (CD62P) binding to PSGL-1 expressed on TAMs and activating the JNK/STAT1 pathway to induce the transcription of C5 and the release of C5a, shifting TAMs toward a protumor phenotype. Inhibiting the C5a/C5aR1 axis or PSGL-1 significantly reduced CRC growth.

Conclusions: An increase in intratumoral platelets promoted CRC growth and metastasis by CD62P binding to PSGL-1 expressed on TAMs, leading to JNK/STAT1 signaling activation, which promoted C5 transcription and activated the C5a/C5aR1 axis in TAMs. Our study examined the mechanism of the crosstalk between platelets and TAMs to exacerbate CRC development and proposed a potential therapeutic strategy for CRC patients.

Keywords: Platelets, TAMs, CRC, PSGL-1/JNK/STAT1, C5a/C5aR1.

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