Lymphoid tissue-resident Alcaligenes LPS induces IgA production without excessive inflammatory responses via weak TLR4 agonist activity.

Alcaligenes are opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer's patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of Alcaligenes LPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by Alcaligenes LPS in vitro or in vivo. Alcaligenes LPS also showed adjuvanticity, inducing antigen-specific immune responses without excessive inflammation. These findings reveal the presence of commensal bacteria-mediated homeostatic inflammatory conditions within PPs that produce optimal IgA induction without causing pathogenic inflammation and suggest that Alcaligenes LPS could be a safe and potent adjuvant.

Innate immunomodulation by lipophilic termini of lipopolysaccharide; synthesis of lipid As from Porphyromonas gingivalis and other bacteria and their immunomodulative responses.

Synthetic studies of lipid A and LPS partial structures have been performed to investigate the relationship between structures and functions of LPS. Recent studies have suggested several pathological implications of LPS from parasitic bacteria due to its influence on the host immune responses. To address this issue, we established an efficient synthetic strategy that is widely applicable to the synthesis of various lipid As by using a key disaccharide intermediate with selectively cleavable protecting groups. Porphyromonas gingivalis and Helicobacter pylori lipid As were synthesized and their biological activities were evaluated. All synthetic lipid As did not induce strong inflammatory responses: some are very weak cytokine inducers and others are antagonistic in IL-6 and IL-8 induction with E. coli LPS. On the other hand, P. gingivalis lipid As showed potent IL-18 inducing activity. Since IL-18 has been shown to correlate with chronic inflammation, P. gingivalis LPS may be implicated in the chronic inflammatory responses.