Cookbraun3050

Upon Salmonella-infection, colocalization of Salmonella, LC3, and linear ubiquitin was detected in parental HeLa cells to induce xenophagy. Treatment with HOIPIN-8 disturbed the colocalization and facilitated Salmonella expansion. In contrast, HOIPIN-8 showed little effect on the colocalization of LC3 and Salmonella in NDP52-knockout cells, suggesting that NDP52 is a weak regulator in LUBAC-mediated xenophagy. These results indicate that the crosstalk between NDP52 and LUBAC regulates innate immune responses, apoptosis, and xenophagy.Visceral leishmaniasis (VL) is a fatal parasitic disease if untreated. Treatment options of VL diminish due to emerging drug resistance. Although the principal host cells for the multiplication of Leishmania are macrophages, neutrophils are the first cells infected with the parasites rapidly after parasite inoculation. Leishmania can survive in neutrophils despite the potent antimicrobial effector functions of neutrophils that can eliminate the parasites. Recently, the growing field of immunometabolism provided strong evidence for the therapeutic potential in targeting metabolic processes as a means of controlling immune effector functions. Therefore, the understanding of the immunometabolic profile of neutrophils during Leishmania infection could provide new promising targets for host-directed therapies against VL. To our knowledge, this is the first study addressing the bioenergetics profile of L. donovani-infected primary human neutrophils. Transcriptome analysis of L. donovani-infected neutrophils revealection. Our results show, that seven days post-infection the parasite load of 2-DG treated animals was significantly higher than in mock treated animals. This data indicates that glycolysis serves as major energy source for antimicrobial effector functions against L. donovani. Inhibition of glycolysis abrogates important neutrophil effector functions that are necessary the initial control of Leishmania infection.Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (S S,1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp2-iminosugar glycolipid (sp2-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (S S)-DS-ONJ in microglia. (S S)-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR.Background The alpha7 nicotinic acetylcholine receptor (Chrna7) plays an essential anti-inflammatory role in immune homeostasis and was recently found on mast cells (MC). Psychosocial stress can trigger MC hyperactivation and increases pro-inflammatory cytokines in target tissues such as the skin. If the cholinergic system (CS) and Chrna7 ligands play a role in these cascades is largely unknown. Objective To elucidate the role of the CS in the response to psychosocial stress using a mouse-model for stress-triggered cutaneous inflammatory circuits. Methods Key CS markers (ACh, Ch, SLURP-1, SLURP-2, Lynx1, Chrm3, Chrna7, Chrna9, ChAT, VAChT, Oct3, AChE, and BChE) in skin and its MC (sMC), MC activation, immune parameters (TNFα, IL1β, IL10, TGFβ, HIF1α, and STAT3) and oxidative stress were analyzed in skin from 24 h noise-stressed mice and in cultured MC (cMC) from C57BL/6 or Chrna7-Knockout mice. Results First, Chrna7 and SLURP-1 mRNA were exclusively upregulated in stressed skin. Second, histomorphometry located Chrna7 and SLURP-1 in nerves and sMC and demonstrated upregulated contacts and increased Chrna7+ sMC in stressed skin, while 5 ng/mL SLURP-1 degranulated cMC. Third, IL1β+ sMC were high in stressed skin, and while SLURP-1 alone had no significant effect on cMC cytokines, it upregulated IL1β in cMC from Chrna7-KO and in IL1β-treated wildtype cMC. In addition, HIF1α+ sMC were high in stressed skin and Chrna7-agonist AR-R 17779 induced ROS in cMC while SLURP-1 upregulated TNFα and IL1β in cMC when HIF1α was blocked. Conclusions These data infer that the CS plays a role in the regulation of stress-sensitive inflammatory responses but may have a surprising pro-inflammatory effect in healthy skin, driving IL1β expression if SLURP-1 is involved.Pro-inflammatory signaling mediated by Toll-like receptor 4 (TLR4)/myeloid differentiation-2 (MD-2) complex plays a crucial role in the instantaneous protection against infectious challenge and largely contributes to recovery from Gram-negative infection. Activation of TLR4 also boosts the adaptive immunity which is implemented in the development of vaccine adjuvants by application of minimally toxic TLR4 activating ligands. The modulation of pro-inflammatory responses via the TLR4 signaling pathway was found beneficial for management of acute and chronic inflammatory disorders including asthma, allergy, arthritis, Alzheimer disease pathology, sepsis, and cancer. The TLR4/MD-2 complex can recognize the terminal motif of Gram-negative bacterial lipopolysaccharide (LPS)-a glycophospholipid lipid A. Although immense progress in understanding the molecular basis of LPS-induced TLR4-mediated signaling has been achieved, gradual, and predictable TLR4 activation by structurally defined ligands has not yet been attaif biological activity, the chemical structure of DLAMs was designed to permit a predefined binding orientation in the binding groove of MD-2, which ensured tailored and species-independent (human and mice) TLR4 activation. Manipulating phosphorylation and acylation pattern at the sugar moiety facing the secondary dimerization interface allowed for adjustable modulation of the TLR4-mediated signaling. Tailored modulation of cellular pro-inflammatory responses by distinct modifications of the molecular structure of DLAMs was attained in primary human and mouse immune cells, lung epithelial cells and TLR4 transfected HEK293 cells.Although the abilities of the omentum to alleviate inflammation and prevent infection have been revealed over the past decades, the underlying mechanisms remain largely unelucidated. Here, we demonstrated that the mortality of mice exposed to cecal ligation and puncture (CLP) and omentectomy was remarkably increased compared to those treated with CLP alone. Moreover, the efficacy of the omentum was associated with an impairment in intraperitoneal bacterial clearance together with an increase in the expression of proinflammatory cytokines. Besides, in response to peritoneal infections, the size and quantity of the omental milky spots (MSs) were increased tremendously and they also support innate-like B1 cell responses and local IgM production in the peritoneal cavity. Furthermore, not only the migration but also the functional activities of neutrophils were diminished in the absence of the omentum. These data collectively show that the omentum contributes more to peritoneal immune responses during septic peritonitis than has heretofore been recognized. Thus, harnessing the function of MS-containing omentum to increase its protective effectiveness may exert important biological and therapeutic implications for the control of intra-abdominal infections.Background Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. Objective To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Methods Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Results Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficie not available in India. Eight (16.3%) patients had so far succumbed to their illness. Conclusions This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.Outbreaks that occur as a result of zoonotic spillover from an animal reservoir continue to highlight the importance of studying the disease interface between species. One Health approaches recognise the interdependence of human and animal health and the environmental interplay. Improving the understanding and prevention of zoonotic diseases may be achieved through greater consideration of these relationships, potentially leading to better health outcomes across species. In this review, special emphasis is given on the emerging and outbreak pathogen Crimean-Congo Haemorrhagic Fever virus (CCHFV) that can cause severe disease in humans. We discuss the efforts undertaken to better understand CCHF and the importance of integrating veterinary and human research for this pathogen. Furthermore, we consider the use of closely related nairoviruses to model human disease caused by CCHFV. We discuss intervention approaches with potential application for managing CCHFV spread, and how this concept may benefit both animal and human health.Although B cells have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA), the precise role of B cells in RA needs to be explored further. Our previous studies have revealed that adiponectin (AD) is expressed at high levels in inflamed synovial joint tissues, and its expression is closely correlated with progressive bone erosion in patients with RA. In this study, we investigated the possible role of AD in B cell proliferation and differentiation. We found that AD stimulation could induce B cell proliferation and differentiation in cell culture. Notably, local intraarticular injection of AD promoted B cell expansion in joint tissues and exacerbated arthritis in mice with collagen-induced arthritis (CIA). Mechanistically, AD induced the activation of PI3K/Akt1 and STAT3 and promoted the proliferation and differentiation of B cells. Moreover, STAT3 bound to the promoter of the Blimp-1 gene, upregulated Blimp-1 expression at the transcriptional level, and promoted B cell differentiation. Collectively, we observed that AD exacerbated CIA by enhancing B cell proliferation and differentiation mediated by the PI3K/Akt1/STAT3 axis.