Distinct Lipid A Moieties Contribute to Pathogen-Induced Site-Specific Vascular Inflammation

Several successful pathogens have evolved mechanisms to evade host defense,resulting in the establishment of persistent and chronic infections. one such pathogen,porphyromonas gingivalis,induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. p. gingivalis expresses an atypical lipopolysaccharide (lps) structure containing heterogeneous lipid a species,that exhibit toll-like receptor-4 (tlr4) agonist or antagonist activity,or are non-activating at tlr4. in this study,we utilized a series of p. gingivalis lipid a mutants to demonstrate that antagonistic lipid a structures enable the pathogen to evade tlr4-mediated bactericidal activity in macrophages resulting in systemic inflammation. production of antagonistic lipid a was associated with the induction of low levels of tlr4-dependent proinflammatory mediators,failed activation of the inflammasome and increased bacterial survival in macrophages. oral infection of apoe-/- mice with the p. gingivalis strain expressing antagonistic lipid a resulted in vascular inflammation,macrophage accumulation and atherosclerosis progression. in contrast,a p. gingivalis strain producing exclusively agonistic lipid a augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner,resulting in host cell lysis and decreased bacterial survival. apoe-/- mice infected with this strain exhibited diminished vascular inflammation,macrophage accumulation,and atherosclerosis progression. notably,the ability of p. gingivalis to induce local inflammatory bone loss was independent of lipid a expression,indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. collectively,our results point to a pivotal role for activation of the non-canonical inflammasome in p. gingivalis infection and demonstrate that p. gingivalis evades immune detection at tlr4 facilitating chronic inflammation in the vasculature. these studies support the emerging concept that pathogen-mediated chronic inflammatory disorders result from specific pathogen-mediated evasion strategies resulting in low-grade chronic inflammation. © 2014 slocum et al.