ABSTRACT
BACKGROUND: While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The physiological implications of these constant transient interactions are poorly understood. Activated platelets induce and amplify immune responses, but platelets may also maintain immune homeostasis in healthy conditions, including maintaining vascular integrity and T helper cell differentiation, meaning that platelets are central to both immune responses and immune quiescence. Clinical data have shown an association between low platelet counts (thrombocytopenia) and immune dysfunction in patients with sepsis and extracorporeal membrane oxygenation, further implicating platelets as more holistic immune regulators, but studies of platelet immune functions in nondisease contexts have had limited study. METHODS: We used in vivo models of thrombocytopenia and in vitro models of platelet and monocyte interactions, as well as RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing), to mechanistically determine how resting platelet and monocyte interactions immune program monocytes. RESULTS: Circulating platelets and monocytes interact in a CD47-dependent manner to regulate monocyte metabolism, histone methylation, and gene expression. Resting platelet-monocyte interactions limit TLR (toll-like receptor) signaling responses in healthy conditions in an innate immune training-like manner. In both human patients with sepsis and mouse sepsis models, thrombocytopenia exacerbated monocyte immune dysfunction, including increased cytokine production. CONCLUSIONS: Thrombocytopenia immune programs monocytes in a manner that may lead to immune dysfunction in the context of sepsis. This is the first demonstration that sterile, endogenous cell interactions between resting platelets and monocytes regulate monocyte metabolism and pathogen responses, demonstrating platelets to be immune rheostats in both health and disease.
Subject(s)
Sepsis , Thrombocytopenia , Mice , Animals , Humans , Monocytes/metabolism , Thrombocytopenia/metabolism , Blood Platelets/metabolism , Immunity , Sepsis/metabolism , Platelet ActivationABSTRACT
Platelets play crucial roles in the development and progression of coronary artery disease (CAD). The triggering receptor expressed in myeloid cells-like transcript-1 (TLT-1) is stored in platelet α granules, and activated platelets release a soluble fragment (sTLT-1). We set out to better characterize the constituent amino acids of sTLT-1 and to evaluate sTLT-1 for use as a biomarker in patients with stable CAD. We evaluated sTLT-1 release using immunoprecipitation and mass spectrometry and employed statistical methods to retrospectively correlate sTLT-1 concentrations, utilizing ELISA in plasma samples from 1510 patients with documented stable CAD. We identified TLT-1 residues to 133 in platelet releasates. ADAM17 cuts TLT-1, suggesting that S136 is the C-terminal amino acid in sTLT-1. Our results revealed that for CAD patients, sTLT-1 levels did not differ significantly according to primary outcomes of death or major cardiac event; however, patients with left ventricular (LV) dysfunction had significantly lower plasma sTLT-1 levels as compared to those with normal LV function (981.62 ± 1141 pg/mL vs. 1247.48 ± 1589 pg/mL; p = 0.003). When patients were stratified based on sTLT-1 peak frequency distribution (544 pg/mL), a significant association with congestive heart failure was identified (OR = 2.94; 1.040-8.282; p = 0.042), which could be explained by LV dysfunction.
Subject(s)
Coronary Artery Disease , Ventricular Dysfunction, Left , Humans , Coronary Artery Disease/genetics , Retrospective Studies , Myeloid Cells , Blood Platelets , Amino AcidsABSTRACT
Introduction: Fracture-dislocations of the proximal interphalangeal joint (PIPJ) can have a significant impact on digital motion and hand function if inappropriately treated. While these injuries are commonly encountered, they can be quite challenging to manage. It is critical to ensure a concentric reduction and early motion when treating these injuries. Case Report: A 17-year-old woman sustained a fracture-dislocation of the PIPJ of the left small finger. Despite a concentric closed reduction, she had pain and a mechanical block to PIPJ motion. Advanced imaging revealed volar plate entrapment in the retrocondylar space. She was treated with open reduction and direct volar plate repair. Postoperatively, the patient had an excellent outcome with no complications. Conclusion: Our case highlights the importance of both performing an anesthetized examination and investigating the etiology of any limitations to motion even if there is an initial acceptable closed reduction.
ABSTRACT
OBJECTIVES: To identify triggering receptor expressed in myeloid cells-like transcript-1 positive (TLT-1+) microparticles (MPs) and evaluate if their presence is associated with clinical outcomes and/or disease severity in acute respiratory distress syndrome (ARDS). DESIGN: Retrospective cohort study. SETTING: ARDS Network clinical trials. PATIENTS: A total of 564 patients were diagnosed with ARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using flow cytometry, we demonstrated the presence of TLT-1+ platelet-derived microparticles (PMP) that bind fibrinogen in plasma samples from fresh donors. We retrospectively quantified TLT-1, glycoprotein (Gp) 1b, or αIIbßIIIa immunopositive microparticles in plasma samples from patients with ARDS enrolled in the ARMA, KARMA, and LARMA (Studies 01 and 03 lower versus higher tidal volume, ketoconazole treatment, and lisofylline treatment Clincial Trials) ARDS Network clinical trials and evaluated the relationship between these measures and clinical outcomes. No associations were found between Gp1b+ MPs and clinical outcomes for any of the cohorts. When stratified by quartile, associations were found for survival, ventilation-free breathing, and thrombocytopenia with αIIbßIIIa+ and TLT-1+ MPs (χ2p < 0.001). Notably, 63 of 64 patients in this study who failed to achieve unassisted breathing had TLT+ PMP in the 75th percentile. In all three cohorts, patients whose TLT+ MP counts were higher than the median had higher Acute Physiology and Chronic Health Evaluation III scores, were more likely to present with thrombocytopenia and were 3.7 times (p < 0.001) more likely to die than patients with lower TLT+ PMP after adjusting for other risk factors. CONCLUSIONS: Although both αIIbßIIIa+ and TLT+ microparticles (αIIbßIIIa, TLT-1) were associated with mortality, TLT-1+ MPs demonstrated stronger correlations with Acute Physiology and Chronic Health Evaluation III scores, unassisted breathing, and multiple system organ failure. These findings warrant further exploration of the mechanistic role of TLT-1+ PMP in ARDS or acute lung injury progression.
Subject(s)
Cell-Derived Microparticles , Respiratory Distress Syndrome , Humans , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/mortality , Male , Female , Retrospective Studies , Middle Aged , Cell-Derived Microparticles/metabolism , Adult , Membrane Glycoproteins/blood , Aged , Cohort Studies , Platelet Glycoprotein GPIb-IX Complex/metabolism , Flow Cytometry , Receptors, ImmunologicABSTRACT
In addition to their well-studied hemostatic functions, platelets are immune cells. Platelets circulate at the interface between the vascular wall and leukocytes, and transient platelet-leukocyte complexes are found in both healthy and disease states, positioning platelets to provide physiologic cues of vascular health and injury. Roles for activated platelets in inducing and amplifying immune responses have received an increasing amount of research attention, but our past studies also showed that normal platelet counts are needed in healthy conditions to maintain immune homeostasis. We have now found that thrombocytopenia (a low platelet count) leads to monocyte dysfunction, independent of the cause of thrombocytopenia, in a manner that is dependent on direct platelet-monocyte CD47 interactions that regulate monocyte immunometabolism and gene expression. Compared to monocytes from mice with normal platelet counts, monocytes from thrombocytopenic mice had increased toll-like receptor (TLR) responses, including increased IL-6 production. Furthermore, ex vivo co-incubation of resting platelets with platelet naïve bone marrow monocytes, induced monocyte metabolic programming and durable changes in TLR agonist responses. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) on monocytes from thrombocytopenic mice showed persistently open chromatin at LPS response genes and resting platelet interactions with monocytes induced histone methylation in a CD47 dependent manner. Using mouse models of thrombocytopenia and sepsis, normal platelet numbers were needed to limit monocyte immune dysregulation and IL6 expression in monocytes from human patients with sepsis also inversely correlated with patient platelet counts. Our studies demonstrate that in healthy conditions, resting platelets maintain monocyte immune tolerance by regulating monocyte immunometabolic processes that lead to epigenetic changes in TLR-related genes. This is also the first demonstration of sterile cell interactions that regulate of innate immune-metabolism and monocyte pathogen responses.