design-cecal-ligation-puncture-intranasal-infection-dual-model-sepsis

Design of Cecal Ligation and Puncture and Intranasal Infection Dual Model of Sepsis-Induced Immunosuppression

Sepsis, a severe and complicated life-threatening infection, is characterized by an imbalance between pro- and anti-inflammatory responses in multiple ...

Army Medical University

Long noncoding RNAs (lncRNAs) regulate gene expression. We investigated the role of lncRNAs in the inflammatory response to bacterial infection in the lungs. We identified the lncRNA MEG3 as a tissue-specific modulator of inflammatory responses during bacterial infection. Among the 10 transcript isoforms of MEG3, transcript 4 (referred to as MEG3-4) encodes the isoform with the lowest abundance in mouse lungs. Nonetheless, we found that MEG3-4 bound to the microRNA miR-138 in a competitive manner with mRNA encoding the proinflammatory cytokine interleukin-1β (IL-1β), thereby increasing IL-1β abundance and intensifying inflammatory responses to bacterial infection in alveolar macrophages and lung epithelial cells in culture and in lung tissue in mice. MEG3-4-mediated sponging of miR-138 in the cytoplasm increased the autocrine activity of IL-1β that subsequently induced a negative feedback mechanism mediated by nuclear factor κB that decreased MEG3-4 abundance and inflammatory cytokine production. This timely reduction in MEG3-4 abundance tempered proinflammatory responses in mice with pulmonary bacterial infection, preventing the progression to sepsis. Together, these findings reveal that MEG3-4 dynamically modulates pulmonary inflammatory responses through transcriptional regulation of immune response genes, extending the decoy and sponge mechanism associated with lncRNAs to antibacterial immunity, which affects both response and disease progression.

MEG3-4 is a miRNA decoy that regulates IL-1β abundance to initiate and then limit inflammation to prevent sepsis during lung infection.

Published data revealed that host genetic variants have a substantial influence on sepsis susceptibility. However, the results have been inconsistent. We aimed to systematically review the published studies and quantitatively evaluate the effects of these variants on the risk of sepsis.

Host genetic variants in sepsis risk: a field synopsis and meta-analysis.

CRISPR-Cas systems as adaptive immunity in bacteria and archaea battle against bacteriophages. However, little is known how CRISPR-Cas systems are precisely regulated to effectively eliminate intruders while not inducing self-reactivity. Here, we identify intrinsic negative modulator of CRISPR-Cas that influences interference and adaptation functions. LasI/RhlI-derived autoinducers activate cas operon by enhancing the binding of virulence factor regulator (Vfr) cis-response elements to cas1 promoter, whereas CdpR represses this intracellular signaling and blocks transcription of cas operon. Importantly, inhibition of Vfr reduces cas1 expression and impairs immunization and immune memory mediated by CRISPR-Cas, leading to more severe phage infection but lower self-targeting activities. In addition, CdpR-mediated LasI/RhlI/Vfr intracellular signaling represses cleavage of bacterial endogenous sequences by impeding Cas3 RNA cleavage activity. Thus, CdpR renders important inhibitory effects on CRISPR-Cas systems to avoid possible self-reactivity but potentially heightening infection risk. Our study provides insight into fine regulation of CRISPR-Cas systems for maintaining homeostasis.

Jianxin Jiang

State Key Laboratory of Trauma,
Burns and Combined Injury,
Institute of Surgery Research,
Daping Hospital,
State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital

Army Medical University

Design of Cecal Ligation and Puncture and Intranasal Infection Dual Model of Sepsis-Induced Immunosuppression

Jianxin Jiang

State Key Laboratory of Trauma,Burns and Combined Injury,Institute of Surgery Research,Daping Hospital,State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital

Army Medical University

Design of Cecal Ligation and Puncture and Intranasal Infection Dual Model of Sepsis-Induced Immunosuppression

State Key Laboratory of Trauma,
Burns and Combined Injury,
Institute of Surgery Research,
Daping Hospital,
State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital