Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of immunity, clearly separate them. Neutrophils are the first immune cells recruited to the site of inflammation, and their action is crucial to limit invasion by microorganisms. Furthermore, they play an essential role in proper resolution of inflammation. When these processes are not tightly regulated, they can trigger positive feedback amplification loops that promote neutrophil activation, leading to significant tissue damage and evolution toward chronic disease. Defective chemotaxis, as observed in Crohn’s disease, can also contribute to the disease through impaired microbe elimination. In addition, through NET production, neutrophils may be involved in thrombo-embolic events frequently observed in IBD patients. While the role of neutrophils has been studied in different animal models of IBD for many years, their contribution to the pathogenesis of IBD remains poorly understood, and no molecules targeting neutrophils are used and validated for the treatment of these pathologies. Therefore, it is crucial to improve our understanding of their mode of action in these particular conditions in order to provide new therapeutic avenues for IBD.

AMP-activated protein kinase (AMPK) α1 is activated in platelets on thrombin or collagen stimulation, and as a consequence, phosphorylates and inhibits acetyl-CoA carboxylase (ACC). Because ACC is crucial for the synthesis of fatty acids, which are essential for platelet activation, we hypothesized that this enzyme plays a central regulatory role in platelet function. To investigate this, we used a double knock-in (DKI) mouse model in which the AMPK phosphorylation sites Ser79 on ACC1 and Ser212 on ACC2 were mutated to prevent AMPK signaling to ACC. Suppression of ACC phosphorylation promoted injury-induced arterial thrombosis in vivo and enhanced thrombus growth ex vivo on collagen-coated surfaces under flow. After collagen stimulation, loss of AMPK-ACC signaling was associated with amplified thromboxane generation and dense granule secretion. ACC DKI platelets had increased arachidonic acid-containing phosphatidylethanolamine plasmalogen lipids. In conclusion, AMPK-ACC signaling is coupled to the control of thrombosis by specifically modulating thromboxane and granule release in response to collagen. It appears to achieve this by increasing platelet phospholipid content required for the generation of arachidonic acid, a key mediator of platelet activation.

Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8 T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.

Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between inflammation and thrombosis. On platelets, P2X1 receptors act to amplify platelet activation and aggregation induced by other platelet agonists. These receptors critically contribute to thrombus stability in small arteries. Besides platelets, studies by our group indicate that these receptors are expressed by neutrophils. They promote neutrophil chemotaxis, both in vitro and in vivo. In a laser-induced injury mouse model of thrombosis, it appears that neutrophils are required to initiate thrombus formation and coagulation activation on inflamed arteriolar endothelia. In this model, by using P2X1−/ − mice, we recently showed that P2X1 receptors, expressed on platelets and neutrophils, play a key role in thrombus growth and fibrin generation. Intriguingly, in a model of endotoxemia, P2X1−/ − mice exhibited aggravated oxidative tissue damage, along with exacerbated thrombocytopenia and increased activation of coagulation, which translated into higher susceptibility to septic shock. Thus, besides its ability to recruit neutrophils and platelets on inflamed endothelia, the P2X1 receptor also contributes to limit the activation of circulating neutrophils under systemic inflammatory conditions. Taken together, these data suggest that P2X1 receptors are involved in the interplay between platelets, neutrophils and thrombosis. We propose that activation of these receptors by ATP on neutrophils and platelets represents a new mechanism that regulates thrombo-inflammation.

Clinical evidence indicates that innate immune cells may contribute to acute coronary syndrome (ACS). Our prospective study aimed at investigating the association of neutrophil phenotypes with ACS. 108 patients were categorized into chronic stable coronary artery disease (n = 37), unstable angina (UA) (n = 19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n = 25), and ST-Elevation Myocardial Infarction (STEMI) (n = 27). At the time of inclusion, blood neutrophil subpopulations were analysed by flow cytometry. Differential blood cell count and plasma levels of neutrophilic soluble markers were recorded at admission and, for half of patients, at six-month follow-up. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio than stable and UA patients (p < 0.0001), which normalized at six-month post-MI. Atypical low-density neutrophils were detected in the blood of the four patient groups. STEMI patients were characterized by elevated percentages of band cells compared to the other patients (p = 0.019). Multivariable logistic regression analysis revealed that plasma levels of total myeloperoxidase was associated with STEMI compared to stable (OR: 1.434; 95% CI: 1.119–1.837; P < 0.0001), UA (1.47; 1.146–1.886; p = 0.002), and NSTEMI (1.213; 1.1–1.134; p = 0.0001) patients, while increased neutrophil side scatter (SSC) signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033–14.184; p = 0.045). Hence, changes in neutrophil phenotype are concomitant to ACS.