Platelet activation stimulates macrophages to enhance ulcerative colitis through PF4/CXCR3 signaling

Niu,Yuxiao; Li,Anhong; Xu,Weihua; Zhang,Rong; Mei,Ruya; Zhang,Langhua; Zhou,Fenmin; Pan,Qin; Yan,Yuzhong

doi:10.3892/ijmm.2025.5519

Platelet activation stimulates macrophages to enhance ulcerative colitis through PF4/CXCR3 signaling

Authors:
- Yuxiao Niu
- Anhong Li
- Weihua Xu
- Rong Zhang
- Ruya Mei
- Langhua Zhang
- Fenmin Zhou
- Qin Pan
- Yuzhong Yan
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Affiliations: Graduate School, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China, Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Zhoupu Hospital, Shanghai 201318, P.R. China, Department of Pharmacy, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China, School of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China, Department of Traditional Chinese Medicine, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China, Shanghai Institute of Pediatric Research, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, P.R. China
Published online on: March 14, 2025 https://doi.org/10.3892/ijmm.2025.5519
Article Number: 78
Copyright: © Niu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Platelets are involved in hemostasis and immune regulation, but little is currently known regarding their role in inflammatory bowel disease. In the present study, the mechanism by which platelet activation affects macrophage C‑X‑C motif chemokine receptor 3 (CXCR3) by releasing platelet factor 4 (PF4), thus aggravating ulcerative colitis (UC) disease progression, was investigated. A dextran sulfate sodium‑induced mouse model showed co‑localization of the platelet marker PF4 with the macrophage M1 marker inducible nitric oxide synthase. Furthermore, co‑culturing platelets with monocytes (THP‑1) in vitro led to the transformation of monocytes into macrophages, as well as the activation of macrophages exhibiting proinflammatory properties. Meanwhile, reverse transcription‑quantitative PCR (RT‑qPCR) showed that inflammatory factors, such as IL‑1β, IL‑6 and TNF‑α were significantly increased in macrophages after platelet co‑culture. It was therefore hypothesized that the PF4/CXCR3 pathway may serve an important role in cell‑to‑cell communication. Furthermore, intervention with PF4 in THP‑1 cells induced the M1 macrophage phenotype and inflammatory cytokine expression, which was consistent with co‑culturing, whereas inhibition of CXCR3 (AMG487) reversed the effects of PF4. In addition, following treatment with PF4, THP‑1 cells were found to be under oxidative stress and apoptosis was enhanced, as determined by detecting reactive oxygen species, mitochondrial membrane potential and Annexin‑V, as well as the classical apoptotic proteins Bcl‑2/Bax/caspase‑3 through western blotting. In addition, changes in MAPK and NF‑κB, two classic inflammatory signaling pathways, were detected. Furthermore, mice were treated with an anti‑platelet medication or CXCR3 inhibitor to observe in vivo inflammatory changes; through phenotypic assessment, immunofluorescence staining, RT‑qPCR and TUNEL assay, it was demonstrated that the PF4/CXCR3 pathway may aggravate inflammation in mice with UC. In conclusion, platelets and macrophages may interact in UC through the PF4/CXCR3 pathway to exacerbate inflammation, providing novel options for the treatment of UC.

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