Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis

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.

Lymphocyte cytosolic protein 2 is a novel prognostic marker in lung adenocarcinoma

“…The study by Yan et al shed light on the development of LCP2-targeted therapeutics for sepsis and revealed the important function of LCP2 in RAGE-mediated proinflammatory signaling. 22 The immune system plays a critical role after tumor occurrence, and tumor development is a multi-gene and multi-stage process that includes important contributions of oncogenes and tumor suppressor genes. Thus, the role of LCP2 in LUAD cells and the tumor microenvironment still needs to be further explored in vitro and in vivo.…”

Luteolin improves vasoconstriction function and survival of septic mice via AMPK/NF-κB pathway

“…CLP was performed to induce sepsis in mice as previously described [ 23 , 24 ]. In brief, The mice were anesthetized with 2% isoflurane and fixed on a 37 °C operating platform.…”

Identification of heptapeptides targeting a lethal bacterial strain in septic mice through an integrative approach

“…The operation details for the PlexArray HT were as described previously. 65 The purified protein samples were prepared at determined concentrations in PBS running buffer, while glycine-HCl buffer (10 mmol/L, pH 2.0) was used for regeneration. Binding data were collected and analyzed by SPR Data Analysis Module software (Plexera, USA).…”