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Self-rechargeable heart failure pacemaker technique together with triboelectric nanogenerators.
The innate immune system senses "non-self" molecules derived from pathogens (PAMPs) as well as endogenous damage-associated molecular patterns (DAMPs) and promotes sterile inflammation that is necessary for injury resolution, tissue repair/regeneration, and homeostasis. The NOD-, LRR- and pyrin domain containing protein 3 (NLRP3) is an innate immune signaling complex whose assembly and activation can be triggered by various signals ranging from microbial molecules to ATP or the abnormal accumulation of crystals, thus leading to IL-1β and IL-18 maturation and secretion. HO-3867 ic50 Deregulation of the NLRP3 signaling cascade is associated with numerous inflammatory and metabolic diseases including rheumatoid arthritis, gout, atherosclerosis or type 2 diabetes. Interestingly, the circadian clock controls numerous inflammatory processes while clock disruption leads to or exacerbates inflammation. Recently, the biological clock was demonstrated to control NLRP3 expression and activation, thereby controlling IL-1β and IL-18 secretion in diverse tissues and immune cells, particularly macrophages. Circadian oscillations of NLRP3 signaling is lost in models of clock disruption, contributing to the development of peritonitis, hepatitis, or colitis. Sterile inflammation is also an important driver of atherosclerosis, and targeting the production of IL-1β has proven to be a promising approach for atherosclerosis management in humans. Interestingly, the extent of injury after fulminant hepatitis or myocardial infarction is time-of-day dependent under the control of the clock, and chronotherapy represents a promising approach for the management of pathologies involving deregulation of NLRP3 signaling.Pathological self-assembly is a concept that is classically associated with amyloids, such as amyloid-β (Aβ) in Alzheimer's disease and α-synuclein in Parkinson's disease. In prokaryotic organisms, amyloids are assembled extracellularly in a similar fashion to human amyloids. Pathogenicity of amyloids is attributed to their ability to transform into several distinct structural states that reflect their downstream biological consequences. While the oligomeric forms of amyloids are thought to be responsible for their cytotoxicity via membrane permeation, their fibrillar conformations are known to interact with the innate immune system to induce inflammation. Furthermore, both eukaryotic and prokaryotic amyloids can self-assemble into molecular chaperones to bind nucleic acids, enabling amplification of Toll-like receptor (TLR) signaling. Recent work has shown that antimicrobial peptides (AMPs) follow a strikingly similar paradigm. Previously, AMPs were thought of as peptides with the primary function of permeatligands bound to AMPs, and immune ligands spatially organized to varying degrees by AMPs, result in different immunologic outcomes. In this framework, not all ordered structures generated during multi-stepped AMP (or amyloid) assembly are pathological in origin. Supramolecular structures formed during this process serve as signatures to the innate immune system to orchestrate immune amplification in a proportional, situation-dependent manner.Rationale Gestational cigarette smoke (CS) impairs lung angiogenesis and alveolarization, promoting transgenerational development of asthma and bronchopulmonary dysplasia (BPD). Hydrogen sulfide (H2S), a proangiogenic, pro-alveolarization, and anti-asthmatic gasotransmitter is synthesized by cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfur transferase (3MST). Objective Determine if gestational CS exposure affected the expression of H2S synthesizing enzymes in the mouse lung and human placenta. Methods Mice were exposed throughout gestational period to secondhand CS (SS) at approximating the dose of CS received by a pregnant woman sitting in a smoking bar for 3 h/days during pregnancy. Lungs from 7-days old control and SS-exposed pups and human placenta from mothers who were either non-smokers or smokers during pregnancy were analyzed for expression of the enzymes. Measurements Mouse lungs and human placentas were examined for the expression of CSE, CBS, and 3MST by immunohistochemical staining, qRT-PCR and/or Western blot (WB) analyses. Results Compared to controls, mouse lung exposed gestationally to SS had significantly lower levels of CSE, CBS, and 3MST. Moreover, the SS-induced suppression of CSE and CBS in F1 lungs was transmitted to the F2 generation without significant change in the magnitude of the suppression. These changes were associated with impaired epithelial-mesenchymal transition (EMT)-a process required for normal lung angiogenesis and alveolarization. Additionally, the placentas from mothers who smoked during pregnancy, expressed significantly lower levels of CSE, CBS, and 3MST, and the effects were partially moderated by quitting smoking during the first trimester. Conclusions Lung H2S synthesizing enzymes are downregulated by gestational CS and the effects are transmitted to F2 progeny. Smoking during pregnancy decreases H2S synthesizing enzymes is human placentas, which may correlate with the increased risk of asthma/BPD in children.Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naïve T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure continued operational readiness of the adaptive immune system. Here, we investigated the molecular and cellular mechanisms of inflammation-induced DC generation. We found that infection with viral and bacterial pathogens as well as Toll-like receptor 9 (TLR9) ligation with CpG-oligodeoxynucleotide (CpG-ODN) expanded an erythropoietin (EPO)-dependent TER119+CD11a+ cell population in the spleen that had the capacity to differentiate into TER119+CD11chigh and TER119-CD11chigh cells both in vitro and in vivo. TER119+CD11chigh cells contributed to the conventional DC pool in the spleen and specifically increased in lymph nodes draining the site of local inflammation. Our results reveal a so far undescribed inflammatory EPO-dependent pathway of DC differentiation and establish a mechanistic link between innate immune recognition of potential immunosuppressive pathogens and the maintenance of the DC pool during and after infection.
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