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

PLoS Pathogens

Ning Hua¹  James A. Hamilton¹  Connie Slocum²  George Papadopoulos²  Caroline A. Genco²  Ellen O. Weinberg²  Carolyn Kramer²  Cynthia V. Gudino²  Stephen R. Coats³  Richard P. Darveau³ 

[1] Department of Biophysics, Boston University School of Medicine, Boston, Massachusetts, United States of America;Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America;Department of Periodontics, School of Dentistry, University of Washington, Seattle, Washington, United States of America

关键词: Lipids;    Lipid structure;    Inflammation;    Macrophages;    Inflammasomes;    Inflammatory diseases;    Immune receptor signaling;    Atherosclerosis;   

DOI  :  10.1371/journal.ppat.1004215

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY