TLRs in Hepatic Cellular Crosstalk

Toll-like receptors (TLRs) are expressed on all major subsets of liver cells. Both exogenous ligands derived from pathogens, and endogenous ligands that are products of cellular injury, engage these receptors and activate aspects of innate immunity. These receptors play a role in viral and parasitic infections of the liver, in ischemia-reperfusion injury, and in toxic liver damage, promoting antipathogen immunity but also hepatocellular injury and fibrogenesis. However, TLRs may also participate in negative feedback that limits tissue injury. In the complex environment of the liver, TLRs participate in pathologic cascades involving multiple cell types, manifesting their effects both through cell-autonomous actions, and via cellular crosstalk. In this paper we survey the involvement of TLRs in these diverse processes

A sub-pixel and multispectral corner detector

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Simulation and tomography analyses of textile composite reinforcement

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Ecotoxicological effect of altered TiO2 nanocomposite on the earthworm, Eisenia fetida

19th Annual VM Goldschmidt Conference, Davos, SWITZERLAND, JUN 21, 2009International audienceno abstrac

TLR4-Dependent Secretion by Hepatic Stellate Cells of the Neutrophil-Chemoattractant CXCL1 Mediates Liver Response to Gut Microbiota

Background & Aims The gut microbiota significantly influences hepatic immunity. Little is known on the precise mechanism by which liver cells mediate recognition of gut microbes at steady state. Here we tested the hypothesis that a specific liver cell population was the sensor and we aimed at deciphering the mechanism by which the activation of TLR4 pathway would mediate liver response to gut microbiota. Methods Using microarrays, we compared total liver gene expression in WT versus TLR4 deficient mice. We performed in situ localization of the major candidate protein, CXCL1. With an innovative technique based on cell sorting, we harvested enriched fractions of KCs, LSECs and HSCs from the same liver. The cytokine secretion profile was quantified in response to low levels of LPS (1ng/mL). Chemotactic activity of stellate cell-derived CXCL1 was assayed in vitro on neutrophils upon TLR4 activation. Results TLR4 deficient liver had reduced levels of one unique chemokine, CXCL1 and subsequent decreased of neutrophil counts. Depletion of gut microbiota mimicked TLR4 deficient phenotype, i.e., decreased neutrophils counts in the liver. All liver cells were responsive to low levels of LPS, but hepatic stellate cells were the major source of chemotactic levels of CXCL1. Neutrophil migration towards secretory hepatic stellate cells required the TLR4 dependent secretion of CXCL1. Conclusions Showing the specific activation of TLR4 and the secretion of one major functional chemokine— CXCL1, the homolog of human IL-8-, we elucidate a new mechanism in which Hepatic Stellate Cells play a central role in the recognition of gut microbes by the liver at steady state.National Institute of Allergy and Infectious Diseases (U.S.) (Grant #1R01AI072049