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Using RNA-interference to Investigate the Innate Immune Response in Mouse Macrophages
Published on: November 3, 2014
Innate immunity to intracellular LPS
Vijay A K Rathinam1, Yue Zhao2, Feng Shao3
1Department of Immunology, UConn Health School of Medicine, Farmington, CT, USA. rathinam@uchc.edu.
Abstract:
Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called 'pyroptosis', which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions.
Insights
The innate immune system detects bacterial lipopolysaccharide (LPS) in the cytosol, activating caspase-11 (and related caspases) to trigger pyroptosis, a cell death mechanism crucial for fighting infection and preventing septic shock.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- The innate immune system monitors cellular compartments for pathogens.
- Cytosolic surveillance pathways often activate caspases, including caspase-1 via inflammasomes.
- Caspase-11 (rodents) and caspase-4/5 (humans) specifically detect intracellular bacterial lipopolysaccharide (LPS).
Purpose of the Study:
- To review the sensing mechanisms of cytosolic LPS.
- To discuss the regulation and pathophysiological functions of this pathway.
- To highlight the role of caspase-11-mediated pyroptosis in host defense.
Main Methods:
- Review of emerging literature on cytosolic LPS sensing.
- Analysis of caspase activation and pyroptosis execution.
- Examination of GSDMD's role in pyroptosis and inflammasome activation.
Main Results:
- Intracellular LPS directly activates caspase-11, caspase-4, and caspase-5.
- Activation of these caspases leads to pyroptosis, a lytic cell death.
- Pyroptosis is executed by GSDMD, which forms pores upon caspase-mediated cleavage.
- GSDMD pore formation can activate the NLRP3 inflammasome, promoting IL-1β and IL-18 maturation.
Conclusions:
- Caspase-11-mediated pyroptosis is essential for antibacterial defense and septic shock.
- The sensing of cytosolic LPS is a critical innate immune mechanism.
- Further research into this pathway holds therapeutic potential for inflammatory diseases.
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