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Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis
Zhengzheng Yan1,2,3, Haihua Luo1, Bingyao Xie1
1Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Abstract:
Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.
Insights
Researchers discovered that SLP76 is crucial for RAGE signaling in sepsis. Targeting SLP76
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Receptor for Advanced Glycation Endproducts (RAGE) plays a key role in sepsis pathogenesis.
- Mechanisms of RAGE signal transduction in septic shock remain unclear.
Purpose of the Study:
- To elucidate the role of SLP76 in RAGE-mediated signaling during sepsis.
- To identify SLP76 as a therapeutic target for sepsis.
Main Methods:
- In vitro and in vivo binding assays to identify RAGE-SLP76 interaction.
- Genetic deficiency models (RAGE or SLP76 knockout) to assess signaling pathways.
- Inhibition studies using TAT-conjugated SAM domain of SLP76.
- Murine model of sepsis (cecal ligation and puncture - CLP) to evaluate therapeutic efficacy.
Main Results:
- SLP76 directly binds to the cytosolic tail of RAGE via its sterile alpha motif (SAM).
- Genetic deficiency of RAGE or SLP76 significantly reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2, and IKKα/β, and lowers cytokine release.
- Delivery of the RAGE-binding SAM domain inhibits pro-inflammatory cytokine production in macrophages.
- Administration of TAT-SAM in CLP mice attenuated inflammatory cytokine release, reduced tissue damage, and improved survival.
Conclusions:
- SLP76 is a critical downstream signaling mediator for RAGE in sepsis.
- The RAGE-SLP76 interaction is essential for pro-inflammatory responses in sepsis.
- Targeting the SLP76-RAGE interaction, specifically the SAM domain, offers a potential therapeutic strategy for sepsis.
