Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Ma, Chi; Fu, Qiong; Diggs, Laurence P.; McVey, John C.; McCallen, Justin D.; Wabitsch, Simon; Ruf, Benjamin; Brown, Zachary J.; Heinrich, Bernd; Zhang, Qianfei; Rosato, Umberto; Wang, Sophie; Cui, Linda L.; Berzofsky, Jay A.; Kleiner, David E.; Bosco, Dale B.; Lai, Chih‐Ming; Rotman, Yaron; Xie, Changqing; Korangy, Firouzeh; Greten, Tim F.

doi:10.1016/j.ccell.2022.08.004

Cited by 38 publications

(46 citation statements)

References 53 publications

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“…Indeed, plasma CD40L has been reported as a biomarker of platelet activation such as PAC-1 and CD62p, and serves as a reliable predictor of sepsis prognosis (Wegrzyn et al 2021). It is estimated that more than 95% of the circulating CD40L originates from activated platelets (Andre et al 2002), and can modulate adaptive immune responses (Ma et al 2022). Since platelet-derived CD40L can activate glial cells to damage the blood-brain barrier in hypertension (Bhat et al 2017), we speculated that the activated platelets induce the intestinal barrier dysfunction, which is associated with the upregulation of CD40L-CD40 pathway in reactive enteric glia during sepsis.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis

Cheng

et al. 2022

Mol Med

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Background Intestinal barrier dysfunction, which is associated with reactive enteric glia cells (EGCs), is not only a result of early sepsis but also a cause of multiple organ dysfunction syndrome. Inhibition of platelet activation has been proposed as a potential treatment for septic patients because of its efficacy in ameliorating the organ damage and barrier dysfunction. During platelet activation, CD40L is translocated from α granules to the platelet surface, serving as a biomarker of platelet activation a reliable predictor of sepsis prognosis. Given that more than 95% of the circulating CD40L originate from activated platelets, the present study aimed to investigate if inhibiting platelet activation mitigates intestinal barrier dysfunction is associated with suppressing reactive EGCs and its underlying mechanism. Methods Cecal ligation and puncture (CLP) was performed to establish the sepsis model. 24 h after CLP, the proportion of activated platelets, the level of sCD40L, the expression of tight-junction proteins, the intestinal barrier function and histological damage of septic mice were analyzed. In vitro, primary cultured EGCs were stimulated by CD40L and LPS for 24 h and EGCs-conditioned medium were collected for Caco-2 cells treatment. The expression of tight-junction proteins and transepithelial electrical resistance of Caco-2 cell were evaluated. Results In vivo, inhibiting platelet activation with cilostazol mitigated the intestinal barrier dysfunction, increased the expression of ZO-1 and occludin and improved the survival rate of septic mice. The efficacy was associated with reduced CD40L+ platelets proportion, decreased sCD40L concentration, and suppressed the activation of EGCs. Comparable results were observed upon treatment with compound 6,877,002, a blocker of CD40L–CD40–TRAF6 signaling pathway. Also, S-nitrosoglutathione supplement reduced intestinal damage both in vivo and in vitro. In addition, CD40L increased release of TNF-α and IL-1β while suppressed the release of S-nitrosoglutathione from EGCs. These EGCs-conditioned medium reduced the expression of ZO-1 and occludin on Caco-2 cells and their transepithelial electrical resistance, which could be reversed by CD40-siRNA and TRAF6-siRNA transfection on EGCs. Conclusions The inhibition of platelet activation is related to the suppression of CD40L-CD40-TRAF6 signaling pathway and the reduction of EGCs activation, which promotes intestinal barrier function and survival in sepsis mice. These results might provide a potential therapeutic strategy and a promising target for sepsis.

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Section: Introductionmentioning

confidence: 99%

Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis

Cheng

et al. 2022

Mol Med

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“…In addition, a single intrathecal injection of P2Y12 antagonists reversed the nerve-injury induced tactile allodynia [ 70 , 71 ]. Since the P2Y12 receptor is also present in the platelets [ 72 , 73 ] and DRG satellite cells, future study is needed to use conditional knockouts of P2Y12 receptors to test the function of microglial specific P2Y12 receptor in inflammatory and neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Spinal microglia contribute to sustained inflammatory pain via amplifying neuronal activity

Murugan

et al. 2022

Mol Brain

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Microglia are highly dynamic immune cells of the central nervous system (CNS). Microglial processes interact with neuronal elements constantly on the order of minutes. The functional significance of this acute microglia-neuron interaction and its potential role in the context of pain is still largely unknown. Here, we found that spinal microglia increased their process motility and electrophysiological reactivity within an hour after the insult in a mouse model of formalin-induced acute, sustained, inflammatory pain. Using an ablation strategy to specifically deplete resident microglia in the CNS, we demonstrate that microglia participate in formalin-induced acute sustained pain behaviors by amplifying neuronal activity in the spinal dorsal horn. Moreover, we identified that the P2Y12 receptor, which is specifically expressed in microglia in the CNS, was required for microglial function in formalin-induced pain. Taken together, our study provides a novel insight into the contribution of microglia and the P2Y12 receptor in inflammatory pain that could be used for potential therapeutic strategies.

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“…Platelets can protect TCs from destruction by shear forces, favor adhesion and extravasation at distant sites, favor immune evasion, mediate a tumor-prone inflammation, or favor neo-angiogenesis (Haemmerle, Stone, Menter, AfsharKharghan, Sood, 2018). While recent work suggests that platelets can control tumor initiation and growth, as shown recently in the liver (Ma et al, 2022; Senft, 2022) and are recruited to ovarian tumors by thrombopoietic cytokines to further fuel tumor growth (Stone et al, 2012), abundant research demonstrates that they mostly promote tumor cell metastasis. A seminal study documented the inhibition of metastasis by platelet depletion, which can be rescued by platelets transfusion (Gasic, Gasic, Stewart, 1968).…”

Section: Introductionmentioning

confidence: 99%

“…They mediate immune evasion, favor adhesion and extravasation at distant sites, facilitate neo-angiogenesis and mediate a tumor-prone inflammation (13). Although recent work suggests that platelets can also hamper tumor initiation and growth, as shown in the liver (14)(15)(16) and ovarian tumors (14), abundant research thus demonstrates that they mostly promote tumor cell metastasis. A seminal study documented the inhibition of metastasis by platelet depletion, which can be rescued by platelets transfusion (17).…”

Section: Introductionmentioning

confidence: 99%

Platelets favor the outgrowth of established metastases

Garcia‐Leon

Follain

Mouriaux

et al. 2022

Preprint

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Despite abundant evidence demonstrating that platelets foster metastasis, a therapeutic approach based on anti-platelet agents is not an option due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subjected syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases. Genetic depletion and pharmacological targeting of the platelet-specific receptor GPVI in humanized mouse models efficiently reduced the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study is the first to demonstrate therapeutic efficacy when targeting animals carrying growing metastases. It further identifies GPVI as the first molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

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Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Cited by 38 publications

References 53 publications

Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis

Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis

Spinal microglia contribute to sustained inflammatory pain via amplifying neuronal activity

Platelets favor the outgrowth of established metastases

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