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TLR signaling pathway. TLRs can be expressed on the surface of cells or inside cells. However, TLRs can activate corresponding signaling pathways through different ligands, and ultimately, they all focus on some common downstream signaling pathways to induce the production of pro-inflammatory cytokines and type I interferon. MD2: Myeloid differentiation protein 2; IRAK: Interleukin-1 receptor-associated kinase; TRAF: TNF receptor-associated factor; PI3K: RIP1: Receptor-interacting protein 1; TAB: TGF-beta-activated kinase 1 and MAP3K7-binding protein; IKKα: Inhibitor of nuclear factor kappa-B kinase subunit alpha; IKKβ: Inhibitor of nuclear factor kappa-B kinase subunit beta; IKBα: I-kappa-B-alpha; NEMO: NF-kappa-B essential modifier; TBK1: Serine/threonine-protein kinase TBK1; for other abbreviations, see Table 1.
Source publication
Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its traditional role in hemostasis and thrombosis, it also plays an indispensable role in inflammatory diseases. However, thrombocytopenia is a common hematologic problem in the clinic, an...
Contexts in source publication
Context 1
... this pathway, TRIF interacts with TRAF3 and TRAF6, but TRAM is thought to interact with TRIF to promote the activation of the TRAF3-dependent kinase TBK1, which then drives IFN induction and interferon-stimulated gene expression. In summary, after different ligands bind to TLRs, the cytoplasmic TIR domain of TLRs recruits the signaling adapters MyD88, TIRAP, TRAM and/or TRIF, which activate different downstream pathways according to different adapters, such as Type I interferons, p38 MAPK and JNK MAPK pathways (Figure 4). ...
Context 2
... 2023, 24, x FOR PEER REVIEW 8 of 26 downstream pathways according to different adapters, such as Type I interferons, p38 MAPK and JNK MAPK pathways (Figure 4). However, TLRs can activate corresponding signaling pathways through different ligands, and ultimately, they all focus on some common downstream signaling pathways to induce the production of pro-inflammatory cytokines and type I interferon. ...
Context 3
... are also key secretors of TLR-triggering DAMPs and, in this capacity, serve as initiators of innate immunity. Moreover, some TLRs are also expressed in megakaryocytes, and their activation not only regulates platelet biogenesis but also regulates pro- Figure 4. TLR signaling pathway. ...
Citations
... Pulmonary megakaryocytes, on the other hand, improve antiviral capacity in humans by enhancing the regulation of type 1 IFN response, and increase PLT aggregation to promote coagulation [43]. Meanwhile, lung megakaryocytes express immune response-related genes such as TLR3, which recognizes double-stranded RNA (dsRNA) associated with viral infection to enhance platelet function and reduce platelet production [44]. Therefore, promoting pulmonary megakaryopoiesis or improving pulmonary megakaryocyte function may serve as a treatment for COVID-19. ...
PLAIN LANGUAGE SUMMARY
What is the context?
Platelets are specialized non-nucleated blood cells produced by cytoplasmic lysis of megakaryocytes.
HSCs differentiate into granular mature megakaryocytes and produce platelets.
Lung is a reservoir of megakaryocytes and a site where platelets are produced in addition to bone marrow and spleen.
Lung injury can be divided into acute lung injury and chronic lung injury, and characterized by different pathogenesis.
Platelets and megakaryocytes are involved in hemostasis and regulation of the body ‘s inflammatory response.
The disease state of the lung affects the functions of megakaryocytes and platelets.
The role of megakaryocytes and platelets in acute and chronic lung injury is poorly studied.
What is new?
Platelets in the lung are derived not only from the spleen and bone marrow, but also from megakaryocytes in the pulmonary circulation. In this study, we demonstrated that pulmonary megakaryocytes not only produce platelets to play a hemostatic role in lung injury, but also participate in inflammation and immune response with platelets to promote the process of lung injury or play a protective role.
Therefore, it was suggested in our analysis that targeting lung megakaryocytes and platelets is currently a new direction for the treatment of a variety of lung injuries.
What is the impact?
This review intends to explain the relationship between megakaryocytes, platelets and many types of lung injury from the mechanism of platelet production in the lung, and make a prospect in the new progress in the diagnosis and treatment of lung injury.
... In this regard, during cytokine storm, the physical interaction between TLR5 and TLR4 directs the signaling pathway towards MyD88-dependent pathway by forming Myddosome (a complex of MyD88 and IRAK4), which activates NF-kB and the expression of associated downstream pro-inflammatory genes (Kumar, 2020;Tang X. et al., 2023). In general, the activation of TLR signaling in response to DAMPs and PAMPs relies on the signaling pathways mediated by MyD88 and TRIF. ...
Infectious diseases are among the factors that account for a significant proportion of disease-related deaths worldwide. The primary treatment approach to combat microbial infections is the use of antibiotics. However, the widespread use of these drugs over the past two decades has led to the emergence of resistant microbial species, making the control of microbial infections a serious challenge. One of the most important solutions in the field of combating infectious diseases is the regulation of the host’s defense system. Toll-like receptors (TLRs) play a crucial role in the first primary defense against pathogens by identifying harmful endogenous molecules released from dying cells and damaged tissues as well as invading microbial agents. Therefore, they play an important role in communicating and regulating innate and adaptive immunity. Of course, excessive activation of TLRs can lead to disruption of immune homeostasis and increase the risk of inflammatory reactions. Targeting TLR signaling pathways has emerged as a new therapeutic approach for infectious diseases based on host-directed therapy (HDT). In recent years, stem cell-derived exosomes have received significant attention as factors regulating the immune system. The regulation effects of exosomes on the immune system are based on the HDT strategy, which is due to their cargoes. In general, the mechanism of action of stem cell-derived exosomes in HDT is by regulating and modulating immunity, promoting tissue regeneration, and reducing host toxicity. One of their most important cargoes is microRNAs, which have been shown to play a significant role in regulating immunity through TLRs. This review investigates the therapeutic properties of stem cell-derived exosomes in combating infections through the interaction between exosomal microRNAs and Toll-like receptors.
... 65 Among the key receptors in the innate immune system, TLR plays a critical role by inducing the release of pro-inflammatory cytokines, initiating the production of inflammatory mediators responsible for pain, fever, and other inflammatory reactions, and exerting regulatory influence over the inflammatory cascade. 66 In cultured astrocytes from mice after spinal nerve ligation (SNL), exposure to IL-1β or TNF-α increased by Tumor necrosis factor receptorassociated factor 6 (TRAF6) levels. TRAF6 is a crucial mediator involved in TLR signaling, NF-κB activation, and the expression of proinflammatory cytokines and interferons. ...
Neuropathic pain is a widespread clinical issue caused by somatosensory nervous system damage, affecting numerous individuals. It poses considerable economic and public health challenges, and managing it can be challenging due to unclear underlying mechanisms. Nevertheless, emerging evidence suggests that neurogenic inflammation and neuroinflammation play a role in developing pain patterns. Emerging evidence suggests that neurogenic inflammation and neuroinflammation play significant roles in developing neuropathic pain within the nervous system. Increased/decreased miRNA expression patterns could affect the progression of neuropathic and inflammatory pain by controlling nerve regeneration, neuroinflammation, and the expression of abnormal ion channels. However, our limited knowledge of miRNA targets hinders a complete grasp of miRNA's functions. Meanwhile, exploring exosomal miRNA, a recently uncovered role, has significantly advanced our comprehension of neuropathic pain's pathophysiology in recent times. In this review, we present a comprehensive overview of the latest miRNA studies and explore the possible ways miRNAs might play a role in the development of neuropathic pain.
... Granulopoiesis is located in the venous sinuses in the bone marrow and is initiated by common myeloid progenitors (CMPs), which are derived from haematopoietic stem cells (HSCs) [34,35]. At this stage, myeloid-progenitor cells have the ability to differentiate into the following pathways: thrombopoiesis, erythropoiesis, monocytopoiesis, formation of mast cells, and granulopoisesis [36,37]. The first cell of the myeloid lineage is a granulocytemonocyte progenitor (GMP)-an oligopotent progenitor that during the following stage differentiates into unipotent-neutrophil-committed-myeloblast cells [29,35]. ...
... Granulopoiesis is located in the venous sinuses in the bone marrow and is initiated by 146 common myeloid progenitors (CMPs) which are derived from haematopoietic stem cells 147 (HSCs) [35,36]. At this stage, myeloid progenitor cells have the ability to differentiate into 148 the following pathways: thrombopoiesis, erythropoiesis, monocytopoiesis, formation of 149 mast cells and granulopoisesis [37,38]. The first cell of the myeloid lineage is a granulocyte-150 monocyte progenitor (GMP) -an oligopotent progenitor which during the following stage 151 differentiates into unipotent neutrophil committed cell -myeloblast [30,36]. ...
Recent years have brought progress in understanding the role of the neutrophil, dispelling the dogma of homogeneous cells mainly involved in the prime defence against pathogens, shedding light on their pathogenic role in inflammatory diseases and on the importance of antineutrophil-cytoplasmic antibodies’ pathogenic role in ANCA-associated vasculitides vasculitis (AAV). Myeloperoxidase (MPO) and proteinase 3 (PR3) expressed in neutrophil granulocytes are the most common targets for ANCAs and contribute to the formation of MPO-ANCAs and PR3-ANCAs which, released to the bloodstream, become an excellent diagnostic tool for AAV. In this study, we focus on increasing the clinical and experimental evidence that supports the pathogenic role of ANCAs in AAV. Additionally, we discuss the diagnostic utility of ANCAs for disease activity and prognosis in AAV. Understanding the central role of ANCAs in AAV is crucial for advancing our knowledge of these complex disorders and developing targeted therapeutic strategies in the era of personalized medicine.
... [13] Other parameters, such as white blood cell (WBC) and platelet were also suggested as markers of inflammatory conditions. [14,15] Since preeclampsia is also associated with some degree of inflammatory burden, [4] it is reasonable to study other inflammatory markers in preeclampsia. In addition, fibrinogen to albumin ratio (FAR) is a new inflammatory marker and has been proven to have excellent predictive value for abortus imminent, [16] systemic lupus erythematosus, [17] and ascending aortic aneurysm. ...
Preeclampsia (PE) is a disorder that affects approximately 5% to 10% of pregnant women. Timely and accurate identification of PE and assessment of its severity are crucial. Therefore, it is necessary to develop predictive indicators which are easily measured in routine antenatal examinations to enable the early detection of PE and assess its severity. We designed a single-center retrospective study in our daily work to assess whether the serum levels of fibrinogen to albumin ratio (FAR), fibrinogen (Fib), albumin (ALB), prothrombin time, calcium (Ca), activated partial thrombin time, creatinine (Cr), D-dimer(D-D), platelet, white blood cell, neutrophil, and lymphocyte counts could help in assessing PE and evaluating its severity. Our findings showed that the serum levels of FAR, Cr, Fib, and D-D were significantly higher in the severe preeclampsia group (sPE) compared with the control and mild preeclampsia groups, whereas the levels of ALB and Ca were significantly lower in sPE patients. In addition, no differences were found between the control and PE groups in terms of prothrombin time, activated partial thrombin time, platelet, white blood cell, neutrophils, and lymphocytes counts. Furthermore, FAR is a novel and better indicator for evaluating the severity of PE, which has not been reported before. And it is an independent risk factor for the development of sPE. In conclusion, the serum levels of FAR, Cr, D-D and Fib were positively correlated with PE, whereas ALB and Ca were negatively correlated with PE severity, which might be valuable in evaluating the severity of PE. FAR proved to be a feasible diagnostic marker for sPE with sensitivity and specificity comparable to those of ALB and Fib.
... One of the most crucial receptors for innate immunity, TLR stimulates the generation of pro-inflammatory cytokines, initiates the synthesis of inflammatory mediators that cause fever, pain, and other inflammation, and exerts some regulatory control over the inflammatory response (Tang et al., 2023). Tumour necrosis factor receptor-associated factor 6 (TRAF6), a critical mediator of TLR signalling, NF-κB Frontiers in Molecular Neuroscience 03 frontiersin.org ...
Neuropathic pain, which results from damage to the somatosensory nervous system, is a global clinical condition that affects many people. Neuropathic pain imposes significant economic and public health burdens and is often difficult to manage because the underlying mechanisms remain unclear. However, mounting evidence indicates a role for neurogenic inflammation and neuroinflammation in pain pattern development. There is increasing evidence that the activation of neurogenic inflammation and neuroinflammation in the nervous system contribute to neuropathic pain. Altered miRNA expression profiles might be involved in the pathogenesis of both inflammatory and neuropathic pain by regulating neuroinflammation, nerve regeneration, and abnormal ion channel expression. However, the lack of knowledge about miRNA target genes prevents a full understanding of the biological functions of miRNAs. At the same time, an extensive study on exosomal miRNA, a newly discovered role, has advanced our understanding of the pathophysiology of neuropathic pain in recent years. This section provides a comprehensive overview of the current understanding of miRNA research and discusses the potential mechanisms of miRNAs in neuropathic pain.
Zinc (Zn) is an important trace element; it is involved in the regulation and maintenance of many physiological functions in organisms and has anti-inflammatory and antioxidant properties.
