Inflammation: Mrp8 and Mrp14 raise the death Toll

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Binding of Toll-like receptor 4 to the neutrophil and monocyte cytoplasmic proteins Mrp8 and Mrp14 and the bacterial antigen lipopolysaccharide (LPS) induces a signaling cascade that leads to septic shock.

Lethal septic shock can occur during bacterial infection as an endpoint to the strong inflammatory response caused by bacterially produced lipopolysaccharide (LPS). At the membrane of phagocytes and other immune cells LPS binds to a complex consisting of CD14, Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2). This interaction initiates a signaling cascade that begins with myeloid differentiation factor 88 (Myd88) translocating to the cell membrane, where it activates interleukin-1 receptor-associated kinase-1 (IRAK-1). Subsequent activation of nuclear factor-κB (NF-κB) transcription factor leads to the expression of inflammation-related genes, notably the cytokine tumor necrosis factor-α (TNF α). Reporting in Nature Medicine, Vogl et al. now show that the calcium-binding S100 family of myeloid-related proteins (Mrp) 8 and 14 cooperate with LPS to activate the TLR4-dependent signaling pathway.

Vogl et al. observed that phagocytes lacking Mrp14 did not express genes such as TNF-α that are transcribed upon stimulation by LPS in wild-type cells. Chromatin immunoprecipitation revealed reduced binding of the NF-κB factors p50 and p65 to the TNF-α promotor, suggesting a role for Mrp14 in the regulation of TNF-α expression. Addition of both Mrp14 and Mrp8, and Mrp8 alone, to Mrp14^-/- cells allowed LPS-induced TNF-α expression. Co-administration of LPS doubled this effect, suggesting that Mrp8 is the active component of the Mrp8–Mrp14 complex and that Mrp14 modulates the actions of Mrp8. Furthermore, Mrp8 and LPS act additively in the expression of inflammation-related genes.

Exposure of cells to Mrp8 led to MyD88 translocation and hyperphosphorylation and activation of IRAK-1. Mouse phagocytes expressing non-functional TLR4 did not respond to Mrp8 or LPS stimulation, and HEK293 cells transfected with TLR4, CD14 and MD2, but not untransfected cells, showed Mrp8- or LPS-induced NF-κB activation. The authors also observed direct binding of Mrp8 to the TLR4–MD2 complex, suggesting that Mrp8 is a phagocyte-derived endogenous ligand for TLR-4 and not for RAGE (receptor for advanced glycation end products) as suggested by other S100 proteins.

Vogl et al. also found that upon LPS injection Mrp14^-/- mice survived significantly longer than wild-type mice, while injection of Mrp8 and the Mrp8–Mrp14 complex reinstated wild-type lethality. This established that the Mrp8–Mrp14 complex has a central role in vivo in eliciting the LPS-induced septic shock response.

The results of Vogl et al. demonstrate that Mrp8 and Mrp14 bind to the TLR4–MD2–CD14 complex, inducing a signaling pathway that culminates in septic shock. Mrp8 and Mrp14 may be promising targets for the treatment of uncontrollable inflammatory processes.

Mirko von Elstermann
Functional Glycomics Gateway

Reference

Vogl, T. et al. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nature Medicine 13, 1042-1049 (2007) | Article | PubMed |