lipid-a and Inflammatory-Bowel-Diseases

Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c

Topics: Animals; Biomarkers; CD11c Antigen; Colitis; Disease Models, Animal; Gastrointestinal Microbiome; Homeostasis; Humans; Immunity, Mucosal; Inflammatory Bowel Diseases; Intestinal Mucosa; Lipid A; Lipopolysaccharides; Mice; Mice, Knockout; Positron-Emission Tomography

Current evidence indicates that the chronic inflammation observed in the intestines of patients with inflammatory bowel disease is due to an aberrant immune response to enteric flora. We have developed a lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and can block the interaction of LPS with the immune system. CRX-526 can prevent the expression of proinflammatory genes stimulated by LPS in vitro. This antagonist activity of CRX-526 is directly related to its structure, particularly secondary fatty acyl chain length. In vivo, CRX-526 treatment blocks the ability of LPS to induce TNF-alpha release. Importantly, treatment with CRX-526 inhibits the development of moderate-to-severe disease in two mouse models of colonic inflammation: the dextran sodium sulfate model and multidrug resistance gene 1a-deficient mice. By blocking the interaction between enteric bacteria and the innate immune system, CRX-526 may be an effective therapeutic molecule for inflammatory bowel disease.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caproates; Cells, Cultured; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Glucosamine; HeLa Cells; Humans; Inflammatory Bowel Diseases; Lipid A; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Monocytes; Receptors, Immunologic; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha