Site-specific neuroimmunologic Toll-like receptor 4 (TLR4) signaling pathways mediating early gastrointestinal dysmotility during endotoxemia

• Applicant: Dr. Bettina Maja Buchholz
• Subject Area: General and Visceral Surgery
• Term: from 2009 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 158312262

Gram-negative bacteria derived lipopolysaccharide (LPS) is a causative agent of gastrointestinal ileus. LPS is the prototypical exogenous ligand of the pattern recognition receptor Toll-like receptor 4 (TLR4), which is abundantly expressed on immune and nonimmune cells. Our recent paradigm shifting results clearly demonstrates that low dose endotoxin induced early ileus is not a leukocyte-driven process but initiated by activated plurifunctional parenchymal cells in the abscence of TLR4-competent immune cells. As the preeminant modulator of gastrointestinal motility, we hypothesize that the enteric nervous system is suitable to efficiently govern early endotoxin ileus in the presence of unchanged gastrointestinal smooth muscle function. Therefore, we will investigate LPS induced ileus and the associated inflammatory response in Tlr4loxP/loxP/Synapsin-I Cretg mice with a selective loss of neuronal TLR4 receptor function. Potentially contributing neural circuits include the enteric, parasympathetic, sympathetic, the intrinsic primary afferents and primary afferents. The potenial TLR4 modulation of extrinsic neural control mechanisms of the gut will be addressed by extrinsic denervation and capsaicin-induced lesion of sensory neurons, as well as a transgenic approach using nociceptor neuron deficient (TRK-Ad) mice.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Anthony J. Bauer