NOD3 Reduces Sepsis-Induced Acute Lung Injury by Regulating the Activation of NLRP3 Inflammasome and the Polarization of Alveolar Macrophages.

The pathogenesis of sepsis-induced Acute lung injury (ALI) progresses rapidly, and no effective treatment drugs are known, resulting in a high mortality rate. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation plays an important role in the pathological progression of ALI, and often coincide with the inflammatory activation and polarization of macrophages. NLR family CARD domain-containing protein 3 (NOD3) was reported protecting against sepsis-induced pulmonary pathological injury and inhibiting the inflammatory response in lung tissue. NOD3 can also inhibit NLRP3 inflammasome activation by competitively inhibiting the binding of pro-caspase-1 to apoptosis-related ASC or reducing NLRP3/cryopyrin-induced ASC speckle formation. In this study, we aimed to explore whether NOD3 decrease sepsis-induced lung injury by interfering with NLRP3 inflammasome activation and regulating alveolar macrophages (AMs) polarization. To investigate whether NOD3 reduce sepsis-induced ALI by inhibiting the activation of NLRP3 inflammasome to regulate the polarization of AMs. Sepsis-induced WT (C57BL/6) and NLRC3-/--C57BL/6 mice ALI models were established by intraperitoneal injection of lipopolysaccharide (LPS). In vitro experiments, AMs and bone marrow-derived macrophages (BMDMs) were isolated from WT and NLRC3-/- mice. Using in vivo and in vitro experiments, we found that NOD3 knockout promoted the sepsis-induced inflammatory response in lung tissue. In addition, NOD3 knockout promoted the activation of the TRAF6-NF-κB signaling pathway and the NLRP3 inflammasome in AMs, enhanced the M1-type polarization of AMs and decreased the M2-type polarization of AMs in sepsis-induced lung injury model mice. NOD3 interfered with NLRP3 inflammasome activation by inhibiting NLRP3 inflammasome assembly or negatively regulating the TRAF6-NF-κB signaling pathway, and regulating the polarization of AMs, thereby alleviating sepsis-induced lung injury.

Zhao Y ，Wu Y ，Qu L ，Hu Y ，Sun S ，Yao R ，Li R ... -  《-》

Loganin alleviates sepsis-induced acute lung injury by regulating macrophage polarization and inhibiting NLRP3 inflammasome activation.

Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Excessive inflammation response plays an important role in sepsis-induced acute lung injury (ALI). Loganin is an iridoid glycoside isolated from Corni fructus and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of loganin in sepsis-induced ALI remains unknown. In the current study, the cecal ligation and puncture (CLP)-induced murine sepsis model was constructed to investigate the anti-inflammatory property of loganin in sepsis-induced ALI. Lipopolysaccharide (LPS)-treated Raw 264.7 cells and primary murine peritoneal macrophages were established to further explore underlying mechanism of loganin. Results showed that intragastrical administration of loganin significantly increased murine survival, reduced the alveolar structure damage and inflammatory cell infiltration. Loganin suppressed the release of the M1 macrophage-associated pro-inflammatory cytokines and induced the activation of M2-type anti-inflammatory cytokines. Besides, loganin dramatically inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1β secretion. Further in vitro studies confirmed that loganin efficiently inhibited M1 macrophage polarization and NLRP3 inflammasome activation by blocking the extra-cellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways. Taken together, the anti-inflammatory effect of loganin in sepsis-induced ALI was associated with the ERK and NF-κB pathway-mediated macrophage polarization and NLRP3 inflammasome activation. Our study offers a favorable mechanistic basis to support the therapeutic potential of loganin in anti-inflammatory diseases, such as sepsis-induced ALI.

Zhang J ，Wang C ，Wang H ，Li X ，Xu J ，Yu K ... -  《-》

ATG16L1 restrains macrophage NLRP3 activation and alveolar epithelial cell injury during septic lung injury.

The lung is the organ most commonly affected by sepsis. Additionally, acute lung injury (ALI) resulting from sepsis is a major cause of death in intensive care units. Macrophages are essential for maintaining normal lung physiological functions and are implicated in various pulmonary diseases. An essential autophagy protein, autophagy-related protein 16-like 1 (ATG16L1), is crucial for the inflammatory activation of macrophages. ATG16L1 expression was measured in lung from mice with sepsis. ALI was induced in myeloid ATG16L1-, NLRP3- and STING-deficient mice by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Using immunofluorescence and flow cytometry to assess the inflammatory status of LPS-treated bone marrow-derived macrophages (BMDMs). A co-culture system of BMDMs and MLE-12 cells was established in vitro. Myeloid ATG16L1-deficient mice exhibited exacerbated septic lung injury and a more intense inflammatory response following LPS treatment. Mechanistically, ATG16L1-deficient macrophages exhibited impaired LC3B lipidation, damaged mitochondria and reactive oxygen species (ROS) accumulation. These abnormalities led to the activation of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), subsequently enhancing proinflammatory response. Overactivated ATG16L1-deficient macrophages aggravated the damage to alveolar epithelial cells and enhanced the release of double-stranded DNA (dsDNA), thereby promoting STING activation and subsequent NLRP3 activation in macrophages, leading to positive feedback activation of macrophage NLRP3 signalling. Scavenging mitochondrial ROS or inhibiting STING activation effectively suppresses NLRP3 activation in macrophages and alleviates ALI. Furthermore, overexpression of myeloid ATG16L1 limits NLRP3 activation and reduces the severity of ALI. Our findings reveal a new role for ATG16L1 in regulating macrophage NLRP3 feedback activation during sepsis, suggesting it as a potential therapeutic target for treating sepsis-induced ALI. Myeloid-specific ATG16L1 deficiency exacerbates sepsis-induced lung injury. ATG16L1-deficient macrophages exhibit impaired LC3B lipidation and ROS accumulation, leading to NLRP3 inflammasome activation. Uncontrolled inflammatory responses in ATG16L1-deficient macrophages aggravate alveolar epithelial cell damage. Alveolar epithelial cells release dsDNA, activating the cGAS-STING-NLRP3 signaling pathway, which subsequently triggers a positive feedback activation of NLRP3. Overexpression of ATG16L1 helps mitigate lung tissue inflammation, offering a novel therapeutic direction for sepsis-induced lung injury.

Bai Y ，Zhan X ，Zhu Q ，Ji X ，Lu Y ，Gao Y ，Li F ，Guan Z ，Zhou H ，Rao Z ... -  《-》

NLRC3 Participates in Inhibiting the Pulmonary Inflammatory Response of Sepsis-Induced Acute Lung Injury.

Li R ，Zhao Y ，Zhang X ，Yang L ，Zou X ... -  《-》

Tangeretin attenuates acute lung injury in septic mice by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis.

Liu Y ，Zhang Y ，You G ，Zheng D ，He Z ，Guo W ，Antonina K ，Shukhrat Z ，Ding B ，Zan J ，Zhang Z ... -  《-》