PMID- 37064877 OWN - NLM STAT- MEDLINE DCOM- 20230418 LR - 20230513 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 13 IP - 6 DP - 2023 TI - Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages. PG - 2040-2056 LID - 10.7150/thno.80555 [doi] AB - 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. CI - (c) The author(s). FAU - Li, Xueqin AU - Li X AD - 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. FAU - Chen, Xin AU - Chen X AD - Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China. FAU - Gong, Shengzhe AU - Gong S AD - 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. AD - National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, Jiangsu, China. FAU - Zhao, Jie AU - Zhao J AD - 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. FAU - Yao, Chen AU - Yao C AD - 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. FAU - Zhu, Hanyong AU - Zhu H AD - 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. FAU - Xiao, Rui AU - Xiao R AD - 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. AD - National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, Jiangsu, China. FAU - Qin, Yongqin AU - Qin Y AD - 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. AD - National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, Jiangsu, China. FAU - Li, Rongqing AU - Li R AD - 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. FAU - Sun, Na AU - Sun N AD - 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. FAU - Li, Xiangyang AU - Li X AD - 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. FAU - Dong, Fuxing AU - Dong F AD - Public Experimental Research Center, Xuzhou Medical University, Xuzhou, Jiangsu, China. FAU - Zhao, Tingting AU - Zhao T AD - Chongqing International Institute for Immunology, Chongqing, China. FAU - Pan, Yuchen AU - Pan Y AD - 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. FAU - Yang, Jing AU - Yang J AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230327 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 80295-54-1 (Complement C5a) RN - 0 (P-selectin ligand protein) RN - 0 (Receptor, Anaphylatoxin C5a) RN - 0 (Stat1 protein, mouse) RN - 0 (STAT1 Transcription Factor) RN - 0 (C5ar1 protein, mouse) SB - IM MH - Mice MH - Animals MH - *Complement C5a/genetics/metabolism MH - *Tumor-Associated Macrophages/metabolism MH - Blood Platelets/metabolism MH - Receptor, Anaphylatoxin C5a MH - STAT1 Transcription Factor/metabolism PMC - PMC10091882 OTO - NOTNLM OT - C5a/C5aR1. OT - CRC OT - PSGL-1/JNK/STAT1 OT - Platelets OT - TAMs COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2023/04/18 06:00 MHDA- 2023/04/18 10:16 PMCR- 2023/01/01 CRDT- 2023/04/17 03:49 PHST- 2022/11/06 00:00 [received] PHST- 2023/03/13 00:00 [accepted] PHST- 2023/04/18 10:16 [medline] PHST- 2023/04/17 03:49 [entrez] PHST- 2023/04/18 06:00 [pubmed] PHST- 2023/01/01 00:00 [pmc-release] AID - thnov13p2040 [pii] AID - 10.7150/thno.80555 [doi] PST - epublish SO - Theranostics. 2023 Mar 27;13(6):2040-2056. doi: 10.7150/thno.80555. eCollection 2023.