Hyperlipidemia Impaired Innate Immune Response to Periodontal Pathogen Porphyromonas gingivalis in Apolipoprotein E Knockout Mice

ABSTRACTRemoval of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. InPorphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes theP. gingivalislipid A deacylase enzyme. This gene, PGN_1123 inP. gingivalis33277, is highly conserved withinP. gingivalis, and putative orthologs are phylogenetically restricted to theBacteroidetesphylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-typeP. gingivalis. Heterologous expression of PGN_1123 inBacteroides thetaiotaomicronpromoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme.IMPORTANCEPeriodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population.Porphyromonas gingivalisis a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection.P. gingivalisis particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.

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Tanshinone IIA Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice Infected with Porphyromonas gingivalis

Inflammation ◽

10.1007/s10753-017-0603-8 ◽

2017 ◽

Vol 40 (5) ◽

pp. 1631-1642 ◽

Cited By ~ 14

Author(s):

Yan Xuan ◽

Yue Gao ◽

Hao Huang ◽

Xiaoxuan Wang ◽

Yu Cai ◽

...

Keyword(s):

Apolipoprotein E ◽

Porphyromonas Gingivalis ◽

Knockout Mice ◽

Tanshinone Iia ◽

Apolipoprotein E Knockout Mice

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Loss of mDia1 Mediates the Development of Del(5q) MDS through Upregulation of the Innate Immune Response and Induction of Neutropenia

Blood ◽

10.1182/blood.v124.21.4617.4617 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4617-4617

Author(s):

Yang Mei ◽

Baobing Zhao ◽

Jing Yang ◽

Peng Ji

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Knockout Mice ◽

Actin Polymerization ◽

Conflicts Of Interest ◽

Innate Immune ◽

Intercellular Adhesion Molecule ◽

Related Phenomenon ◽

Mrna Levels ◽

Age Related

Abstract mDia1, the diaphanous homolog 1 of Drosophila in mouse, is a formin protein involving in the linear actin polymerization. Recently, our group reported that patients with del(5q) myelodysplastic syndromes (MDS) showed a significantly decreased mDia1 expression. Mice with mDia1 deficiency developed age related hematologic features mimicking human MDS. In these mice, CD14 is aberrantly overexpressed on granulocytes, which sensitized the innate immune response upon the lipopolysaccharide(LPS) injection. Importantly, chronic LPS injection accelerated the development of MDS (Keerthivasan et al Blood 2014). Here we report that 1) the mDia1 knockout (KO) mice also have a hypersensitive innate immune response to damage-associated molecular pattern molecules (DAMPs), which can be partially blocked by CD14/Toll-like receptor 4(TLR4) signaling pathway inhibitors. This is significant since release of DAMPs from necrotic or senescent cells is a common age-related phenomenon. DAMPs are also detected in cancers including MDS. Thus our study may shed lights on how the deregulated innate immune responses get involved in the pathogenesis of MDS in a more pathophysiologically relevant etiology. 2) mDia1 KO mice have an increased Gr1/Mac1 expression on the granulocytes in peripheral blood. We demonstrate that the expression levels of Gr1/Mac1 were not changed in bone marrow granulocytes, suggesting a specific up-regulation of Gr1/Mac1 levels on circulating granulocytes in mDia1 knockout mice. Mac-1, as the predominant β2 integrin on granulocytes, plays key roles in the adhesion of leukocytes to the endothelium, and regulates the cell adhesion, migration, and chemotaxis. In this respect, the mDia1 knockout mice develop serve neutropenia, which could be due to the upregulation of Gr1/Mac1 and increased binding of the cells to intercellular adhesion molecule-1 (ICAM-1). Finally, we revealed the mechanism of Gr1/Mac1 upregulation by showing that loss of mDia1 significantly affected the endocytosis of Gr1 and Mac1 on granulocytes, however, the mRNA levels of Gr1 and Mac1 were not affected. Taken together, these studies reveal a significance of loss of mDia1 in the pathogenesis of del(5q) MDS through upregulation of innate immune response and accelerated granulocyte clearance. Disclosures No relevant conflicts of interest to declare.

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