Daily Sepsis Research Analysis
Three mechanistic sepsis studies advance our understanding of immunothrombosis and inflammatory cell death. New work identifies RING1 as a ubiquitin ligase that restrains GSDMD-driven pyroptosis, shows platelet NLRP6 limits microvascular thrombosis via a TRIM21–TAB1–NF-κB axis, and links fatty acid synthesis to endothelial mtDNA release that activates cGAS–STING in sepsis-induced lung injury.
Summary
Three mechanistic sepsis studies advance our understanding of immunothrombosis and inflammatory cell death. New work identifies RING1 as a ubiquitin ligase that restrains GSDMD-driven pyroptosis, shows platelet NLRP6 limits microvascular thrombosis via a TRIM21–TAB1–NF-κB axis, and links fatty acid synthesis to endothelial mtDNA release that activates cGAS–STING in sepsis-induced lung injury.
Research Themes
- Regulation of pyroptosis via ubiquitination of GSDMD
- Platelet innate immune signaling and immunothrombosis in sepsis
- Metabolic control of endothelial injury through mtDNA release and cGAS–STING
Selected Articles
1. RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection.
The study identifies RING1 as an E3 ligase that directly ubiquitinates GSDMD (K48-linked at K51/K168) to limit pyroptosis. Ring1 deficiency worsened LPS-induced sepsis and Salmonella infection and led to dysregulated responses in tuberculosis, positioning RING1 as a regulator of inflammatory cell death and a potential therapeutic target.
Impact: This work uncovers a nodal control of pyroptosis with direct therapeutic implications for sepsis and infectious diseases by targeting the RING1–GSDMD axis.
Clinical Implications: Modulating RING1 activity could calibrate excessive pyroptosis in septic shock, but strategies must balance pathogen clearance versus immunopathology; biomarkers of RING1/GSDMD activity may aid endotyping.
Key Findings
- RING1, but not RING2, promotes K48-linked ubiquitination of GSDMD at K51 and K168, driving proteasomal degradation and limiting pyroptosis.
- Ring1 knockout mice exhibit increased mortality and bacterial burden with S. typhimurium, exacerbated LPS-induced sepsis, and dysregulated responses to M. tuberculosis.
- Pharmacologic or genetic inhibition of RING1 elevates GSDMD and pyroptotic cell death, nominating RING1 as a potential therapeutic target.
Methodological Strengths
- Multi-model in vivo validation across LPS sepsis and bacterial infections (Salmonella, M. tuberculosis)
- Precise mechanistic mapping including identification of GSDMD ubiquitination sites (K51/K168) and functional consequences
Limitations
- Preclinical models without human interventional data; translational applicability remains to be tested
- Context-dependent effects across pathogens could complicate therapeutic targeting
Future Directions: Develop selective RING1 modulators; define sepsis endotypes with dysregulated RING1–GSDMD signaling; evaluate safety-efficacy trade-offs in large-animal models and early-phase trials.
RING1 is an E3 ligase component of the polycomb repressive complex 1 (PRC1) with known roles in chromatin regulation and cellular processes such as apoptosis and autophagy. However, its involvement in inflammation and pyroptosis remains elusive. Here, we demonstrate that human RING1, not RING2, promotes K48-linked ubiquitination of Gasdermin D (GSDMD) and acts as a negative regulator of pyroptosis and bacterial infection. Indeed, we showed that loss of Ring1 increased S. typhimurium infectious load and mortality in vivo. Though RING1 deletion initially reduced M. tuberculosis (Mtb) infectious load in vivo, increased lung inflammation and impaired immune defense responses were later observed. Moreover, Ring1 knockout exacerbated acute sepsis induced by lipopolysaccharide (LPS) in vivo. Mechanistically, RING1 directly interacts with GSDMD and ubiquitinates the K51 and K168 sites of GSDMD for K48-linked proteasomal degradation, thereby inhibiting pyroptosis. Inhibition of RING1 E3 ligase activity by direct mutation or with the use of small molecule inhibitors increased GSDMD level and cell death during pyroptosis. Our findings reveal that RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection, highlighting RING1 as a potential therapeutic target for combating infectious diseases.
2. Platelet NLRP6 protects against microvascular thrombosis in sepsis.
Platelet-specific NLRP6 restrains immunothrombosis in sepsis by promoting TRIM21-mediated K48-linked ubiquitination and degradation of TAB1, thereby dampening NF-κB signaling, platelet activation, and NET formation. Loss of platelet NLRP6 worsened survival and microvascular thrombosis in CLP sepsis, highlighting a platelet-intrinsic protective pathway.
Impact: This study uncovers a platelet-intrinsic NLR pathway that limits sepsis-related microthrombosis, providing a mechanistic target to modulate immunothrombosis without broadly suppressing immunity.
Clinical Implications: Therapeutic strategies enhancing platelet NLRP6 function or targeting the TAB1–NF-κB axis may reduce microvascular thrombosis and organ injury in sepsis; human translational studies are warranted.
Key Findings
- Platelet-specific NLRP6 deletion increased mortality and microvascular thrombosis in lung and liver in CLP-induced sepsis.
- NLRP6 promotes TRIM21–TAB1 interaction leading to K48-linked polyubiquitination and degradation of TAB1, restraining platelet NF-κB signaling.
- NF-κB inhibition rescued the prothrombotic phenotype of NLRP6-deficient platelets and improved survival; sepsis plasma triggers NLRP6/TRIM21-dependent TAB1 degradation via TLR4/MyD88.
Methodological Strengths
- Platelet-specific knockout with in vivo CLP sepsis model and survival outcomes
- Mechanistic dissection of TRIM21–TAB1–NF-κB pathway with rescue by NF-κB inhibition and human platelet ex vivo validation
Limitations
- Findings are largely in murine models; limited human validation with sepsis plasma and healthy platelets
- Potential bleeding risks or off-target effects of pathway modulation are not addressed
Future Directions: Define pharmacologic strategies to boost platelet NLRP6 signaling or mimic TAB1 degradation; assess biomarkers of platelet NF-κB activity as predictors of immunothrombosis in sepsis.
Sepsis is characterized by a systemic inflammation and microvascular thrombosis induced by infection. The nucleotide-oligomerization domain-like receptor family pyrin domain containing 6 protein (NLRP6) possesses both proinflammatory and anti-inflammatory abilities with cell type-specific or tissue-specific functions. However, the role of cell type-specific NLRP6 in sepsis remains poorly understood. In this study, we detected NLRP6 expression in platelets. By using platelet-specific NLRP6 knockout mice and the cecal ligation and puncture model of sepsis, we demonstrated that deletion of platelet NLRP6 increased the mortality; enhanced microvascular thrombosis in the lung and liver; and promoted platelet activation, platelet-neutrophil interactions, as well as the neutrophil extracellular trap (NET) formation after sepsis. Platelet function analysis in vitro showed that deletion of NLRP6 enhanced platelet aggregation, activation, and granules release. In addition, NLRP6 deletion promoted platelet NF-κB signaling via sustaining transforming growth factor-β activated kinase 1-binding protein 1 (TAB1) expression independent of the inflammasome. Moreover, inhibition of NF-κB signaling abolished the aggravated effects of the absence of platelet NLRP6 on the intravascular microthrombosis and NET formation in sepsis and increased the overall survival. Mechanistically, NLRP6 facilitated the interaction between tripartite motif-containing protein 21 (TRIM21) and TAB1 in activated platelets, resulting in K48-linked polyubiquitination of TAB1 and subsequent degradation. Finally, sepsis plasma triggered TAB1 degradation mediated by NLRP6/TRIM21 in normal healthy platelets through toll-like receptor 4/myeloid differentiation primary response 88. Our study identifies a novel protective role of platelet NLRP6 in microvascular thrombosis during sepsis, implying it as a novel target for the treatment of sepsis.
3. Fatty acid synthesis promotes mtDNA release via ETS1-mediated oligomerization of VDAC1 facilitating endothelial dysfunction in sepsis-induced lung injury.
Disordered fatty acid synthesis in sepsis drives endothelial dysfunction by promoting ETS1-dependent VDAC1 oligomerization, mtDNA release, and consequent cGAS–STING activation and pyroptosis. Pharmacologic inhibition of fatty acid synthesis attenuated endothelial injury and lung damage in vitro and in vivo.
Impact: This study mechanistically links cellular metabolism to innate DNA sensing and inflammatory cell death in endothelial injury, revealing actionable targets (FASN, VDAC1, cGAS–STING) for sepsis-associated lung injury.
Clinical Implications: Existing inhibitors of fatty acid synthesis or interventions modulating VDAC1–cGAS–STING may be repurposed to limit endothelial injury in septic lung damage; translational biomarker strategies (mtDNA, lipid signatures) could guide patient selection.
Key Findings
- Fatty acid synthesis is markedly dysregulated in patients with sepsis; its inhibition reduces endothelial and lung injury in vitro and in vivo.
- Fatty acid synthesis promotes ETS1-mediated suppression of VDAC1 ubiquitination, enabling VDAC1 oligomerization and mtDNA release.
- Released mtDNA activates cGAS–STING signaling and endothelial pyroptosis, driving inflammatory and coagulation activation.
Methodological Strengths
- Integrated patient observations with mechanistic in vitro and in vivo experiments
- Clear pathway delineation from metabolic perturbation to VDAC1, mtDNA release, cGAS–STING activation, and pyroptosis
Limitations
- Specific inhibitors and dosing regimens require safety and efficacy validation in humans
- Extent of generalizability across sepsis endotypes and other organs remains uncertain
Future Directions: Evaluate FASN/VDAC1/cGAS–STING modulators in large-animal sepsis models; develop translational biomarkers (circulating mtDNA, lipidomics) to stratify patients for metabolic-endothelial targeting.
Sepsis involves endothelial cell dysfunction leading to the development of lung injury. Fatty acid synthesis contributes to the development of inflammatory injury in sepsis. However, the regulatory mechanisms of fatty acid synthesis-related endothelial activation remain unclear. In this study, we found that fatty acid synthesis in patients with sepsis was greatly disordered. Inhibition of fatty acid synthesis significantly alleviated sepsis-induced endothelial damage and lung injury both in vitro and in vivo. We further found that the release of mtDNA participated in fatty acid synthesis-related regulation of endothelial inflammatory and coagulation activation. Mechanistically, fatty acid synthesis promoted the oligomerization of voltage-dependent anion channel 1 (VDAC1) via ETS proto-oncogene 1 (ETS1)-mediated inhibition of VDAC1 ubiquitination, thereby leading to the increased release of mtDNA and subsequent activation of cGAS-STING signaling and pyroptosis in endothelial cells. Our findings revealed that fatty acid synthesis promoted endothelial dysfunction through mtDNA release, providing new insight into the therapeutic strategies for treating sepsis-associated lung injury.