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关键词： filgotinib   IL-17A   JAK1   pulmonary fibrosis   SOCS3   STAT3  

摘要： BackgroundRegulatory agencies in Europe and Japan have approved filgotinib, a selective JAK1 inhibitor, for use in treating rheumatoid arthritis, but its effect and mechanism of action in treating pulmonary fibrosis remain unclear. MethodsWe performed an in vivo investigation in rats on filgotinib's effect on pulmonary fibrosis resulting from the intratracheal infusion of bleomycin (BLM). Then, we focused on the mechanisms by which filgotinib inhibits experimentally induced pulmonary fibrosis in vitro by determining its effect on TGF-beta 1-induced proliferation of mouse lung fibroblasts. ResultsContinuous gavage of filgotinib at 20 mg/kg for 14 days elicited protective effects in the BLM-induced rat experimental pulmonary fibrosis model, as reflected in changes in Hounsfield units as an indicator of overall pulmonary function and in the lung coefficient and lung microscopic pathology scores as indicators of gross pulmonary pathology. Protein expression levels of IL-17A, phosphorylated tyrosine kinase (p-JAK1), p-STAT3 and cytokine signal transduction inhibitor 3 (SOCS3) were also changed. In in vitro studies, filgotinib at 1 mu M reduced TGF-beta 1-induced fibroblast proliferation and produced lower levels of IL-17A, p-JAK1 and p-STAT3, but higher SOCS3. ConclusionsFilgotinib appeared to alleviate experimental pulmonary fibrosis by reducing fibroblast proliferation via inhibition of the JAK1/STAT3/SOCS3/IL-17A pathway.

摘要： Periodontitis is associated with aspiration pneumonia. However, the relationship between periodontitis and aspiration pneumonia remains unclear. This study investigated the virulence factor of Porphyromonas gingivalis, which exacerbates aspiration pneumonia, and the role of IL-35, an inhibitory heterodimeric cytokine of Epstein-Barr virus-induced gene 3 (EBI3) and p35, in aspiration pneumonia using Ebi3 knockout (KO) mice. Aspiration pneumonia was induced by the intratracheal injection of Streptococcus pneumoniae and P. gingivalis culture supernatant (mixed infection). Leupeptin was used to inhibit gingipain, a virulence factor of P. gingivalis. Four days after infection, lung tissues were collected for analyses. The percentage of interstitium in the group with mixed infection and leupeptin treatment was significantly reduced compared with the nonleupeptin administration group. Additionally, the percentage of interstitium in the field of Ebi3 KO mice was significantly increased compared with wild-type (WT) mice in mixed infection. IL-35 production in WT mice with mixed infection was significantly increased compared with the control group. IL-17 production in Ebi3 KO mice was significantly increased compared with WT mice with mixed infection. These findings suggest that gingipain exacerbates aspiration pneumonia and that IL-35 may contribute to suppressing the exacerbation of aspiration pneumonia. (Am J Pathol 2025, 195: 652-662;https://***/10.1016/ ***.2024.11.009)

关键词： DM9 domain   Pattern recognition receptor   Complement system   Interleukin 17   Oysters  

摘要： DM9 domain-containing protein (DM9CP) as pattern recognition molecule is involved in regulating the inflammation-related signaling pathway in invertebrates. In the present study, a DM9CP with two tandem DM9 repeats (designated as CgDM9CP-8) was identified from Crassostrea gigas. The mRNA transcript of CgDM9CP-8 was the highest in haemocytes. Recombinant CgDM9CP-8 was able to bind various PAMPs (MAN, PGN and LPS) and microbes (Vibrio splendidus, Staphylococcus aureus, Bacillus subtilis, Pichia pastoris, and Yarrowia lipolytica). CgDM9CP-8 protein was distributed in haemocytes and cell-free haemolymph. After lipopolysaccharide (LPS) or V. splendidus stimulation, the mRNA expressions of CgDM9CP-8 in haemocytes were significantly up-regulated at 3 and 6 h, respectively. rCgDM9CP-8 exhibited binding activity to V. splendidus and E. coli, inhibiting their growth in vitro. CgDM9CP-8 was able to bind CgMASPL-1 both in vivo and in vitro to lead to complement CgC3 cleavage. In addition, in CgDM9CP-8-RNAi oysters, the mRNA expressions of interleukin 17s (CgIL17s) in haemocytes decreased significantly after V. splendidus stimulation. These results suggested that CgDM9CP-8 functioned as a pattern recognition and antibacterial molecule to regulate the mRNA expressions of CgIL17s through the activation of CgC3 in C. gigas.

关键词： Hemorrhagic fever with renal syndrome   Endothelial cells   Hantavirus   Hantavirus pulmonary syndrome   Secretion   Vascular permeability   Pathogenesis   Blood plasma  

摘要： Background Hantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. Here, we investigated a potential role for IL-6 trans-signaling in hantavirus *** Effects of IL-6 trans-signaling during in vitro hantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to *** In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did *** IL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of severe HFRS and perhaps also HPS.

关键词： alcoholic cirrhosis   alcohol-related liver disease   ALD   cirrhosis   liver disease   steatotic liver disease  

摘要： Background: There are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD. Aims: We aimed to assess the safety and tolerability of guselkumab in patients with ALD. Methods: This phase-1 dose-escalation study included patients with >= 2 DSM-5 criteria for alcohol use disorder, significant steatosis (MRI-PDFF >= 8%) and MRE < 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose-limiting toxicity. Results: We enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49-61] years. The median MRI-PDFF and MRE were 18.4% [IQR 8.4%-34.0%] and 2.5 [2.2-2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)-17, IL-23, IL-1b and TNF-alpha in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT-C: 6 [3-7] vs. 5 [1-6], p = 0.023). Conclusions: Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.