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Stimulation of erythroleukaemia cell differentiation by extracellular high-mobility group-box protein 1 is independent of the receptor for advanced glycation end-products.

ABSTRACT: In several cell types the binding of extracellular high-mobility group-box protein 1 (HMGB1) with the receptor for advanced glycation end-products (RAGE) induces cytoskeletal reorganization and cell motility. To establish whether RAGE is also involved in murine erythroleukaemia (MEL) cell differentiation stimulated by HMGB1, we have demonstrated that these cells express a 51 kDa protein identified as RAGE, and then we have produced stable transfectants overexpressing wild-type (wt) RAGE or a dominant negative (dn) RAGE mutant lacking the cytoplasmic domain to analyse the differentiation process in these cells. Several experimental findings indicated that RAGE was not involved in the MEL cell differentiation programme. This was also supported by the identical stimulatory effect exerted by HMGB1 on both wt- or dn-RAGE transfectants. We have also observed that HMGB1 binds a 65 kDa protein on the surface of MEL cells, supporting the hypothesis that alternative targets of HMGB1 are expressed on the MEL cell membrane and may be involved as mediators of its signalling.

SUBMITTER: Sparatore B

PROVIDER: S-EPMC1222505 | biostudies-other | 2002 May

REPOSITORIES: biostudies-other

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Project description:High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) increased in response to liver injury. Because HMGB1 is a ligand for the receptor for advanced glycation endproducts (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis though RAGE cell-specific signaling mechanisms. Liver HMGB1 protein expression correlated with fibrosis stage in patients with chronic hepatitis C virus (HCV) infection, primary biliary cirrhosis (PBC), or alcoholic steatohepatitis (ASH). Hepatic HMGB1 protein expression and secretion increased in five mouse models of liver fibrosis attributed to drug-induced liver injury (DILI), cholestasis, ASH, or nonalcoholic steatohepatitis (NASH). HMGB1 was up-regulated and secreted mostly by hepatocytes and Kupffer cells (KCs) following CCl4 treatment. Neutralization of HMGB1 protected, whereas injection of recombinant HMGB1 promoted liver fibrosis. Hmgb1 ablation in hepatocytes (Hmgb1?Hep ) or in myeloid cells (Hmgb1?Mye ) partially protected, whereas ablation in both (Hmgb1?Hep?Mye ) prevented liver fibrosis in vivo. Coculture with hepatocytes or KCs from CCl4 -injected wild-type (WT) mice up-regulated Collagen type I production by hepatic stellate cells (HSCs); yet, coculture with hepatocytes from CCl4 -injected Hmgb1?Hep or with KCs from CCl4 -injected Hmgb1?Mye mice partially blunted this effect. Rage ablation in HSCs (Rage?HSC ) and RAGE neutralization prevented liver fibrosis. Last, we identified that HMGB1 stimulated HSC migration and signaled through RAGE to up-regulate Collagen type I expression by activating the phosphorylated mitogen-activated protein kinase kinase (pMEK)1/2, phosphorylated extracellular signal-regulated kinase (pERK)1/2 and pcJun signaling pathway. Conclusion: Hepatocyte and KC-derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling through RAGE in HSCs to activate the pMEK1/2, pERK1/2 and pcJun pathway and increase Collagen type I deposition.

Project description:Vagal sensory neurons contribute to the symptoms and pathogenesis of inflammatory pulmonary diseases through processes that involve changes to their morphological and functional characteristics. The alarmin high mobility group box-1 (HMGB1) is an early mediator of pulmonary inflammation and can have actions on neurons in a range of inflammatory settings. We hypothesized that HMGB1 can regulate the growth and function of vagal sensory neurons and we set out to investigate this and the mechanisms involved. Culturing primary vagal sensory neurons from wildtype mice in the presence of HMGB1 significantly increased neurite outgrowth, while acute application of HMGB1 to isolated neurons under patch clamp electrophysiological investigation produced inward currents and enhanced action potential firing. Transcriptional analyses revealed the expression of the cognate HMGB1 receptors, Receptor for Advanced Glycation End products (RAGE) and Toll-like Receptor 4 (TLR4), in subsets of vagal sensory neurons. HMGB1-evoked growth and electrophysiological responses were significantly reduced in primary vagal sensory neurons harvested from RAGE deficient mice and completely absent in neurons from RAGE/TLR4 double deficient mice. Immunohistochemical analysis of vagal sensory neurons collected from mice after intranasal infection with murine pneumovirus or influenza A virus (IAV), or after intratracheal administration with the viral mimetic PolyI:C, revealed a significant increase in nuclear-to-cytoplasm translocation of HMGB1 compared to mock-inoculated mice. Neurons cultured from virus infected wildtype mice displayed a significant increase in neurite outgrowth, which was not observed for neurons from virus infected RAGE or RAGE/TLR4 deficient mice. These data suggest that HMGB1 can enhance vagal sensory neuron growth and excitability, acting primarily via sensory neuron RAGE. Activation of the HMGB1-RAGE axis in vagal sensory neurons could be an important mechanism leading to vagal hyperinnervation and hypersensitivity in chronic pulmonary disease.

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Stimulation of erythroleukaemia cell differentiation by extracellular high-mobility group-box protein 1 is independent of the receptor for advanced glycation end-products.

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