Biology subjects

Ture, S. K.

Publications and source records attributed to Ture, S. K..

5 recordsLinked to original sources

bioRxiv2025

Neonatal Platelets Differentiate Monocytes to a Myeloid Derived Suppressor Cell Phenotype

Adult platelets are relatively enriched in immune related molecules compared to neonatal platelets, but neonatal platelets express some growth factors and enzymes at comparatively higher levels. This makes a prediction of platelet-immune cell interaction outcomes in neonates a challenge, as they are likely dependent on the cell type and tissue environment at the time of injury or infection. Our past studies revealed that the transfusion of adult but not neonatal platelets into thrombocytopenic neonatal mice led to an acute increase in monocyte trafficking. We have now found that neonatal, but not adult platelets, induce monocytes to a Myeloid Derived Suppressor Cell (MDSC) phenotype, typified by increased PD-L1, that limits T-cell activation in vitro and in vivo. Monocytes prior incubated with neonatal, but not adult platelets, or platelet releasates, limited T-cell activation in vitro. Using an in vivo asthma-like model we also found that the treatment of mice with monocytes prior incubated with neonatal platelet releasates limited T-cell activation in a asthma-like model. Platelet-driven effects were dependent on neonatal platelets producing more PGE2 that signaled through monocyte EP4. These studies indicate that neonatal platelets have immune limiting roles in the post-natal period by indirectly limiting T-cell responses, perhaps contributing to the adverse outcomes of platelet transfusions to neonates.

immunology↗

bioRxiv2024

Lung megakaryocytes are long-lived, arise from Flt3-negative bone marrow cells, and contribute to platelet recovery in thrombocytopenia

We previously characterized lung megakaryocytes (Mks) as largely extravascular cells with an immune modulatory phenotype (Pariser et al., 2021). Because bone marrow (BM) Mks are relatively short lived, it is assumed that extravascular lung Mks are constantly seeded from the BM, but there are no experimental data to validate this concept. To investigate lung Mk origin and how their origin may impact lung Mk functions, we developed novel models using CFSE dye delivered oropharyngeal (OP) and biotin labeling to specifically label lung Mks and identify lung Mk derived platelets. Labeled lung Mks were present for up to four months, while BM Mks had a less than 1 week lifespan. In a parabiosis model, lung Mks were only partially replaced by a circulating source over a 1-month time period. Unlike tissue resident lung macrophages, we determined using MDS1-Cre-ERT2 TdTomato mice that lung Mks arise from a hematopoietic stem cell (HSC) source. However, studies with FlkSwitch mTmG mice showed that lung Mks originate from a Flt3-negative cell lineage, that does not go through a multipotent progenitor stage. CFSE labeling of lung cells enabled us to track lung Mk-derived platelets and we found that about 10% of circulating platelets at steady-state are lung resident Mk-derived, but in the context of sterile thrombocytopenia there was a doubling of lung Mk derived platelets (about 20%). Lung-derived platelets were similarly increased in a murine malaria infection model (Plasmodium yoelii) typified by chronic thrombocytopenia. Taken together, our studies indicate that lung Mks arise from a Flt3-negative, HSC-dependent pathway and contribute relatively more platelets during thrombocytopenia.

cell biology↗

bioRxiv2023

Thrombocytopenia Independently Leads to Monocyte Immune Dysfunction

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 naive 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.

immunology↗

bioRxiv2023

Monocyte-derived Dll4 is a novel contributor to persistent systemic inflammation in HIV patients

BackgroundIn people living with HIV (PLWH) on combination antiretroviral therapy (cART), persistent systemic inflammation is a driving force for the progression of comorbidities, such as cardiovascular and cerebrovascular diseases. In this context, monocyte- and macrophage-related inflammation rather than T cell activation is a major cause of chronic inflammation. However, the underlying mechanism of how monocytes cause persistent systemic inflammation in PLWH is elusive. Methods and ResultsIn vitro, we demonstrated that lipopolysaccharides (LPS) or tumor necrosis factor alpha (TNF), induced a robust increase of Delta-like ligand 4 (Dll4) mRNA and protein expression in human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Enhanced membrane-bound Dll4 (mDll4) expression in monocytes triggered Notch1 activation to promote pro-inflammatory factors expression. Dll4 silencing and inhibition of Nocth1 activation diminished the LPS or TNF -induced inflammation. exDll4 releases in response to cytokines occurred in monocytes but not endothelial cells or T cells. In clinical specimens, we found that PLWH, both male and female, on cART, showed a significant increase in mDll4 expression, activation of Dll4-Notch1 signaling, and inflammatory markers in monocytes. Although there was no sex effect on mDII4 in PLWH, plasma exDll4 was significantly elevated in males but not females compared to HIV uninfected individuals. Furthermore, exDll4 plasma levels paralleled with monocytes mDll4 in male PLWH. Circulating exDll4 was also positively associated with pro-inflammatory monocytes phenotype and negatively associated with classic monocytes phenotype in male PLWH. ConclusionPro-inflammatory stimuli increase Dll4 expression and Dll4-Notch1 signaling activation in monocytes and enhance monocyte proinflammatory phenotype, contributing to persistent systemic inflammation in male and female PLWH. Therefore, monocyte mDll4 could be a potential biomarker and therapeutic target of systemic inflammation. Plasma exDll4 may also play an additional role in systemic inflammation but primarily in men.

molecular biology↗

bioRxiv2018

Acetylcholine inhibits platelet activation and regulates hemostasis

Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but there are fewer identified endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO). Acetylcholinesterase inhibitors such as donepezil can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets.\n\nWe measured the effect of acetylcholine or analogues of acetylcholine upon human platelet activation ex vivo. We characterized expression of components of the acetylcholine signaling pathway in human platelets. We tested the effect of a subunit of the acetylcholine receptor, CHRNA7, on acetylcholine signaling in platelets. Acetylcholine and analogues of acetylcholine inhibited platelet activation, as measured by P-selectin translocation and GPIIbIIIA conformational changes. Conversely, we found that antagonists of the acetylcholine receptor such as pancuronium enhance platelet activation. Furthermore, drugs inhibiting acetylcholinesterase such as donepezil also inhibit platelet activation, suggesting that platelets release acetylcholine. We found that NO mediates acetylcholine inhibition of platelets. Human platelets express members of the acetylcholine signaling pathway including CHRNA2, CHRNA7, CHRNB1, and ACHE. Platelets from mice lacking Chrna7 are hyperactive when stimulated by thrombin and resistant to inhibition by acetylcholine. Furthermore, acetylcholinesterase inhibitors prolonged bleeding in wild-type mice. Knockout mice lacking Chrna7 subunits of the acetylcholine receptor display prolonged bleeding as well.\n\nOur data suggest that acetylcholine is an endogenous inhibitor of platelet activation. The cholinergic system may be a novel target for anti-thrombotic therapies.

pharmacology and toxicology↗