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关键词： systemic sclerosis   microvasculopathy   fibrosis   immune dysregulation   avenciguat   inflammation   interferon  

摘要： Objectives The soluble guanylate cyclase (sGC) stimulator riociguat is approved for the treatment of pulmonary arterial hypertension and may have antifibrotic effects. However, in fibrotic tissues, oxidative stress and hypoxia can render sGC insensitive to sGC stimulators. sGC activators overcome this limitation. Here, we characterize the novel sGC activator, avenciguat, in preclinical models of *** Human microvascular endothelial cells-dermal (HMVEC-d) cultured in hypoxic conditions and activated human platelet-rich plasma were incubated with varying doses of avenciguat, and the levels of TGF-beta 2 and human CXC chemokine family ligand 4 (CXCL4) were measured, respectively. Treatment with avenciguat was analysed in mice with bleomycin-induced dermal and pulmonary *** Avenciguat reduced hypoxia-induced synthesis of TGF-beta 2 by HMVEC-d and inhibited CXCL4 release by platelets. Moreover, avenciguat demonstrated antifibrotic effects on bleomycin-induced dermal and pulmonary fibrosis. RNA sequencing of affected skin uncovered a unique profile distinguishing avenciguat from riociguat. Avenciguat treatment resulted in deeper regulation of IFN-1 signalling and genes associated with immune response vs riociguat *** In preclinical studies, avenciguat shows the potential to influence vascular, fibrotic and immune-related processes in murine models of SSc. These studies suggest that it may offer therapeutic benefit across multiple aspects of SSc pathophysiology and support the rationale for further investigation in a Phase II clinical trial (VITALISScE (TM);NCT05559580) of avenciguat in SSc.

关键词： colony stimulating factor-1   colony stimulating factor-1 receptor   interleukin-34   microglia   oligodendrocyte progenitor cells   white matter  

摘要： Colony stimulating factor-1 receptor (CSF-1R) signaling is necessary for microglia development and maintenance throughout life. The CSF-1R ligands, CSF-1 and interleukin-34 (IL-34), are indispensable for microglia survival in white matter and gray matter, respectively. While CSF-1 has been studied to a greater extent, the role of IL-34 in microglia function and in the brain overall is much less understood. Here, we examined the region-specific effects of intracerebroventricular (i.c.v.) CSF-1 and IL-34 administration on microglia and oligodendrocyte lineage cells in mice at two timepoints. At 3 days post-intervention, IL-34 increased microglial CD68 levels and the microglia population in the hippocampal CA1 region, whereas CSF-1 increased the microglia population in the corpus callosum. Furthermore, CSF-1, but not IL-34, reduced the oligodendrocyte progenitor cell population in the corpus callosum. These effects were no longer observed at 7 days, revealing the transient nature of the microglial response. Together, these findings demonstrate that in addition to relying on specific signals for survival, microglia respond differently to CSF-1R ligands in a brain microenvironment-dependent manner. These findings highlight the need to better understand microglia in the context of their location, which could provide key insights into the pathogenesis of neuroimmune disorders that predominantly affect gray matter or white matter ***

关键词： Pelteobagrus fulvidraco   Interleukin 21   Interleukin 21 receptor   Molecular cloning   Gene expression   Intestinal immunity  

摘要： Interleukin 21 (IL-21) is a member of the IL-2 family and a pleiotropic cytokine that exerts its effects by binding to its receptor complex (IL-21R alpha and gamma chain). Due to the critical role and multifunctionality of IL-21, its functions have been extensively studied in mammals;however, there has been limited research on IL-21 in teleosts. In this study, the cDNA sequences of Pf_IL-21, Pf_IL-21R alpha.1, Pf_IL-21R alpha.2, Pf_gamma c1 and Pf_gamma c2 genes were cloned from yellow catfish (Pelteobagrus fulvidraco). Four alpha-helices and two q-helices were found in Pf_IL-21, one alpha-helices and three q-helices were found in Pf_IL-21R alpha.1/2, and four alpha-helices and three q-helices were found in Pf_gamma c1/2. Quantitative real-time PCR analysis revealed high levels of mRNA expressions of Pf_IL-21 and its four receptors in mucosal and immune-related tissues of healthy yellow catfish. The mRNA expressions of these five genes in peripheral blood leukocytes (PBLs) were found to be regulated after stimulation with lipopolysaccharides (LPS), phytohaemagglutinin (PHA) and polyinosinic-polycytidylic acid (Poly I:C). Following Edwardsiella ictaluri infection, the mRNA expressions of these genes were significantly up-regulated in peripheral blood, hindgut, swim bladder, and other mucosal or immune-related tissues. In addition, the impact of recombinant (r) Pf_IL-21 protein on the intestinal microbiota and histological structure following E. ictaluri infection was examined. The results showed that E. ictaluri infection resulted in a decline in intestinal microbiota richness and diversity, while Fusobacteriota and Cetobacterium abnormally increased, and hindgut exhibited significant pathological alterations. However, the injection of rPf_IL-21 led to a restoration of intestinal microbiota richness and diversity, accompanied by an increase in certain beneficial bacteria and a better recovery of the hindgut structure. These findings suggest that Pf_IL-21 and its four

关键词： Agmatine   Sepsis   Intestinal injury   AhR   Anti-inflammation  

摘要： Background: Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. However, no reports of AGM alleviating sepsis-related intestinal injury have been found. Therefore, this study intends to investigate the protective effects of AGM on sepsis-related intestinal injury and its potential mechanism. Methods: We first established a sepsis model by lipopolysaccharide (LPS) or cecum ligation perforation (CLP), and then used H&E staining, transmission electron microscopy (TEM), and TUNEL to examine the pathological changes in rat intestines after AGM treatment. ELISA was used to detect expression levels of inflammatory factors in ileal tissues and biochemical indexes of infectionin in serum. TNF-alpha induced Caco-2 cell inflammation model was established in vitro, and cell activity and proliferative capacity were detected by CCK8 and EdU after AGM treatment. The Caco-2 cell inflammation model with high or low expression of Aryl hydrocarbon receptor (AhR) was established, and whether AGM exerts anti-inflammatory effects via AhR/STAT3/IL-10 pathway was investigated using molecular docking, Co-IP, and Western Blot. Results: The histopathological staining demonstrated that AGM significantly reduced intestinal injury and the content of inflammatory factors IL-1(3, IL-6, and TNF-alpha, improved systemic infection and the survival rate of septic mice, and restored intestinal barrier function in CLP rats. In vitro, AGM improved cell viability and proliferative capacity of the Caco-2 cell inflammation model. AGM inhibits inflammatory factor expression by activating AhR, decreasing HIF-1 protein expression, and activating the STAT3/IL-10 signaling pathway. Discussion and conclusion: AGM has the potential to ameliorate sepsis-related intestinal injury via the AhR-STAT3IL-10 pathway, thereby offering theoretical basis for clinical treatm

关键词： Allergy   Contact hypersensitivity   Inflammatory skin diseases   T cells   Transcription factors  

摘要： A plethora of data supports a major role of CD4+ and CD8+ T lymphocytes for the initiation, progression, and maintenance of allergic contact dermatitis. However, in-depth understanding of the molecular mechanisms is still limited. NFATc1 plays an essential role in T-cell activation. We therefore investigated its impact on contact hypersensitivity, the mouse model for allergic contact dermatitis. The contact hypersensitivity response to 2,4,6-trinitrochlorobenzene was diminished in Nfatc1fl/flxCd4-cre mice (Nfatc1-/-) compared with that in wild-type mice and associated with a lower percentage of IL-17-producing CD8+ T (Tc17) cells in both inflamed skin and draining lymph nodes. In vitro Tc17 polarization assays revealed that Nfatc1-/- CD8+ T cells have a reduced capacity to polarize into Tc17 cells. Applying single-cell RNA sequencing, we realized that NFATc1 controls the T-cell differentiation fate. In the absence of NFATc1, CD8+ T cells favor the development of IFN-g-secreting CD8+ T (Tc1) lymphocytes, whereas in its presence, they turn into Tc17 cells. Finally, the adoptive transfer of 2,4,6-trinitrochlorobenzene-sensitized wild-type CD8+ T cells restored the contact hypersensitivity response in na & imath;ve Nfatc1-/- mice. Our data demonstrate that NFATc1 contributes to the development of Tc17 cells and might present a promising target to alleviate CD8+ T-cell-mediated allergic responses.

关键词： antigen presentation   food allergy   IL-9   MHC class II   mucosal mast cell  

摘要： Background IgE-mediated food allergy is accompanied by mucosal mast cell (MMC) hyperplasia in the intestinal mucosa. Intestinal MMC numbers correlate with the severity of food allergy symptoms. However, the mechanisms by which MMCs proliferate excessively are poorly understood. Here, we clarify the role of newly identified MHC class II (MHCII)-expressing MMCs in the effector phase of IgE-mediated food *** Mice reconstituted with MHCII-deficient or wild-type MMCs were used to generate a mouse mode of IgE-mediated food allergy. We assessed the extent of intestinal MMC hyperplasia and the severity of hypothermia in these mice. In addition, we performed in vitro antigen presentation assay using induced MHCII-expressing MMCs generated from bone marrow cells to evaluate the effect of CD4+ T cell activation on MMC *** In food-allergic mice, we identified the appearance of MHCII-expressing MMCs in the intestinal mucosa and showed that MMC hyperplasia was suppressed in mice with MHCII-deficient MMCs compared to mice with wild-type MMCs. In vitro assays demonstrated that MHCII-expressing MMCs incorporate food antigens directly and through the high-affinity IgE receptor Fc epsilon RI-mediated endocytosis and activate antigen-specific CD4+ T cells from food-allergic mice by antigen presentation. Activated CD4+ T cells secrete IL-4 and large amounts of IL-5, which enhance production of the mast cell growth factor IL-9 by IL-33-activated MMCs. Excess IL-9 causes excessive MMC proliferation, leading to the development of MMC *** Antigen presentation to CD4+ T cells by MHCII-expressing MMCs triggers intestinal MMC hyperplasia and exacerbates IgE-mediated food allergy.