DOCK2 protects against bacterial sepsis by constraining T helper 1 response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1266715 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Sepsis is a systemic host response to infection with life-threatening consequence, which ranks among the top 10 causes of death worldwide. Nevertheless, our understanding of the molecular and cellular impact of sepsis remains rudimentary. Here, we identified dedicator of cytokinesis 2 (DOCK2) is a critical downregulating factor for lipopolysaccharide (LPS) signal pathways. DOCK2-deficient mice were highly sensitive to LPS-induced sepsis and Escherichia coli sepsis with increased levels of inflammatory cytokines, especially interferon-g (IFN-g), which were mainly due to hyperresponsive T helper 1 (Th1) cells. Ulteriorly, we verified the vital role of DOCK2-mediated Th1 cells in sepsis by neutralizing both IFN-g and CD4 and found both of which blockade reduced the severity of sepsis in Dock2-/- mice. Mechanically, DOCK2-mediated cell cycle progression and cytokine signaling act in concert to govern peripheral Th1 cell fate. Taken together, our data indicate that DOCK2 acts as a protective role in regulating systemic inflammation and multi-organ injury in bacterial sepsis by constraining Th1 response.
2025-05-22 | GSE297913 | GEO
Project description:Artesunate Protects against Sepsis-induced Cardiomyopathy
| PRJNA1406122 | ENA
Project description:Xijiao Dihuang decoction protects against sepsis-induced cardiac dysfunction
| PRJNA891339 | ENA
Project description:Dedicator of cytokinesis 2 (Dock2), a guanine nucleotide exchange factor that activates the small GTPase Rac1, plays a crucial role in host defense and cytoskeletal regulation. While Dock2 is predominantly expressed in intestinal T cells and is significantly upregulated in patients with inflammatory bowel diseases (IBD), its precise role in intestinal inflammation remains obscure. In this study, we demonstrate that systemic Dock2-deficient mice and T cell-specific Dock2 conditional knockout (Dock2-cKO) mice exhibit exacerbated chemically induced colitis compared to wild-type (WT) controls. Dock2 deficiency led to a substantial reduction in both total and IFN-γ-producing CD8+ T cells, accompanied by elevated colonic IL-22 levels, increased expression of Reg3γ and Reg3β antimicrobial peptides (AMPs), and diminished colonization by Verrucomicrobia, particularly Akkermansia muciniphila (A. muciniphila), at steady state. The expression of Reg3γ&β was suppressed in IL-22- and RORγt-deficient mice, and these AMPs exhibited antimicrobial activity against the expansion and intestinal colonization of A. muciniphila. Co-housing Dock2-cKO mice with WT mice or reintroducing A. muciniphila restored colitis severity to levels comparable to WT mice. The inhibitor against Dock2-Rac1 signaling significantly impaired IFN-γ production in both murine and human T cells. Furthermore, IFN-γ suppressed IL-22 expression induced by IL-1, likely via aryl hydrocarbon receptor (Ahr)-dependent but RORγt-independent mechanisms. Collectively, these findings reveal a critical Dock2-mediated axis linking T cell type 1 responses, IL-22–Reg3 AMPs, and commensal microbiota, particularly A. muciniphila. Targeting Dock2 and its downstream pathways may offer novel therapeutic strategies for IBD and other mucosal-associated immune disorders.
2026-06-10 | GSE288392 | GEO
Project description:Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis characterized by acute and reversible myocardial dysfunction, for which effective targeted therapies remain limited. Artesunate (ART), a well-established first-line antimalarial agent, has attracted increasing attention for its anti-inflammatory, antioxidant, and cytoprotective properties. However, its role in SICM has not been fully elucidated. In this study, a murine SICM model was established using lipopolysaccharide to evaluate the effects of ART on animal mortality, cardiac function, histopathology, and biomarkers of myocardial injury.
2026-01-21 | GSE317118 | GEO
Project description:γ-secretase is a transmembrane protease complex responsible for processing multiple type I transmembrane proteins, including the amyloid precursor protein and NOTCH. Despite various γ-secretase inhibitors and modulators developed in the past decades to target Notch-dependent cancers, their clinical use is still limited due to the low substrate specificity and on-target gut toxicity. Using a proteomics-based screening approach, we found that the dedicator of cytokinesis protein 2 (DOCK2) interacts with the γ-secretase complex component Nicastrin, regulating Nicastrin N45-mannosidation and γ-secretase activity towards NOTCH receptors.
2026-07-31 | PXD057036 | Pride
Project description:Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease, however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARa is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARa in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARa levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARa agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARa function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point towards new therapeutic leads in sepsis.
2019-11-23 | GSE139484 | GEO
Project description:Aberrant activated T cell infiltration is a key driver of autoimmune pathogenesis, highlighting the therapeutic potential of inhibiting T cell migration. However, the regulatory mechanisms governing tissue ingress of antigen-specific T cells remain elusive. Here, we report that SUB1, a transcription factor upregulated in CD4+ T cells from patients with autoimmune disorders, is regulated by the TCR–IRF4 axis. SUB1 deficiency diminished DOCK2 expression by 50%, impairing Rac-dependent actin polymerization and T cell migration, and consequently suppressed the onset of experimental autoimmune encephalomyelitis (EAE). Mechanistically, SUB1 promotes chromatin accessibility at the Junb and Dock2 loci via liquid–liquid phase separation (LLPS), facilitating biomolecular condensate formation. Furthermore, SUB1 directly activates Junb transcription and cooperates with JUNB to enhance Dock2 expression. Our results identify SUB1 as a critical regulator of antigen-specific CD4+ T cell migration and propose it as a promising therapeutic target for autoimmune diseases.
2026-02-01 | GSE309052 | GEO
Project description:Transcriptomic data linked to our study showing that DOCK2 sets the threshold for entry into the virtual memory CD8+ T cell compartment by negatively regulating tonic TCR triggering
2019-10-16 | GSE135594 | GEO
Project description:Aberrant activated T cell infiltration is a key driver of autoimmune pathogenesis, highlighting the therapeutic potential of inhibiting T cell migration. However, the regulatory mechanisms governing tissue ingress of antigen-specific T cells remain elusive. Here, we report that SUB1, a transcription factor upregulated in CD4+ T cells from patients with autoimmune disorders, is regulated by the TCR–IRF4 axis. SUB1 deficiency diminished DOCK2 expression by 50%, impairing Rac-dependent actin polymerization and T cell migration, and consequently suppressed the onset of experimental autoimmune encephalomyelitis (EAE). Mechanistically, SUB1 promotes chromatin accessibility at the Junb and Dock2 loci via liquid–liquid phase separation (LLPS), facilitating biomolecular condensate formation. Furthermore, SUB1 directly activates Junb transcription and cooperates with JUNB to enhance Dock2 expression. Our results identify SUB1 as a critical regulator of antigen-specific CD4+ T cell migration and propose it as a promising therapeutic target for autoimmune diseases.
2026-02-01 | GSE308747 | GEO