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Negative regulation of TLR4 signaling by GIV/Girdin shapes macrophage inflammatory responses


Various insults (e.g. bacterial/viral infection, foreign bodies, or trauma) can trigger an acute inflammatory response which is generally protective; it contains and extinguishes the insult/trigger, removes damaged tissues, and prompts tissue repair. However, an uncontrolled or prolonged inflammatory response can lead to excessive tissue destruction and is a pathologic hallmark of inflammatory diseases including sepsis, arthritis, inflammatory bowel disease (IBD), organ fibrosis, type-II-diabetes, and cancers. Toll-like receptor 4 (TLR4) signaling in response to the Gram-negative bacterial antigen lipopolysaccharide (LPS) is a powerful inducer of inflammatory responses in macrophages and is critical for the control of bacterial infections and re-establishment of tissue homeostasis. However, uncontrolled activation of TLR4 can result in acute sepsis, and contribute to chronic inflammatory diseases. Therefore, understanding the intricate regulatory mechanisms of TLR4 inflammatory responses is essential for development of novel therapeutics combating inflammation-driven disease. In this work, we describe a novel mechanism for negative regulation of TLR4 signaling by the Guanine Exchange Modulator (GEM) family member, GIV, and its impact on macrophage inflammatory responses both in vitro and in vivo animal models of inflammatory disease.

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