Abstract
Macrophages (MΦs) determine oral mucosal responses; mediating tolerance to commensal microbes and food whilst maintaining the capacity to activate immune defences to pathogens. MΦ responses are determined by both differentiation and activation stimuli, giving rise to two distinct subsets; pro-inflammatory M1- and anti-inflammatory/regulatory M2- MΦs. M2-like subsets predominate tolerance induction whereas M1 MΦs predominate in inflammatory pathologies, mediating destructive inflammatory mechanisms, such as those in chronic P.gingivalis (PG) periodontal infection. MΦ responses can be suppressed to benefit either the host or the pathogen. Chronic stimulation by bacterial pathogen associated molecular patterns (PAMPs), such as LPS, is well established to induce tolerance. The aim of this study was to investigate the susceptibility of MΦ subsets to suppression by P. gingivalis. CD14hi and CD14lo M1- and M2-like MΦs were generated in vitro from the THP-1 monocyte cell line by differentiation with PMA and vitamin D3, respectively. MΦ subsets were pre-treated with heat-killed PG (HKPG) and PG-LPS prior to stimulation by bacterial PAMPs. Modulation of inflammation was measured by TNFα, IL-1β, IL-6, IL-10 ELISA and NFκB activation by reporter gene assay. HKPG and PG-LPS differentially suppress PAMP-induced TNFα, IL-6 and IL-10 but fail to suppress IL-1β expression in M1 and M2 MΦs. In addition, P.gingivalis suppressed NFκB activation in CD14lo and CD14hi M2 regulatory MΦs and CD14lo M1 MΦs whereas CD14hi M1 pro-inflammatory MΦs were refractory to suppression. In conclusion, P.gingivalis selectively tolerises regulatory M2 MΦs with little effect on pro-inflammatory CD14hi M1 MΦs; differential suppression facilitating immunopathology at the expense of immunity.
Highlights
Chronic periodontitis (CP) is a persistent inflammatory condition of the periodontal tissues resulting in destruction of the periodontium which, if left untreated, could result in tooth loss
Cross-tolerisation has been described between different microbial species, their pathogen associated molecular patterns (PAMPs) and the corresponding PRRs, which may have a role to play in the inflammatory process of CP, which, in addition to P. gingivalis, is generally driven by a collection of oral pathogens
In addition to the suggestion of cross-tolerisation exhibited between heat-killed PG (HKPG), Porphyromonas gingivalis (PG)-LPS and lipoteichoic acid (LTA) and the differing suppression observed between these PAMPs in the previous table, it was desirable to investigate this process with respect to the bacterial cell wall PAMP, peptidoglycan (PGN)
Summary
Chronic periodontitis (CP) is a persistent inflammatory condition of the periodontal tissues resulting in destruction of the periodontium which, if left untreated, could result in tooth loss. CP results as a consequence of the host inflammatory response to persistent microbial challenge represented by a dysbiotic biofilm in which Porphyromonas gingivalis (PG) is an important member [1,2,3]. PG is an intracellular oral mucosal pathogen which evades recognition and uptake by neutrophils, infecting oral epithelial cells, fibroblasts and underlying dendritic cells and macrophages (MWs) [4,5,6]. Clearance of such intracellular pathogens would necessitate cell mediated immunity, involving Th1 subset cells. PG subverts both adaptive and innate immune function to survive in oral mucosal tissue
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