Paper - Review
10.3389/fcimb.2019.00262
DOI: 10.3389/fcimb.2019.00262
Abstract
Periodontitis
→ is a common intra-oral infection
→ is in-extricably linked → to systemic diseases
The regulation
← between 1⃣ host immunologic response 2⃣ periodontal pathogens
→ has become a host → to explain
→ 1⃣ the mechanism of periodontitis 2⃣ related systemic diseases
Pg.
← Porphyromonas gingivalis
→ was proved as → critical periodontal pathogen above all
The direct release of virulent factors
← in the development of periodontitis
← by periodontal pathogens
→ to destroy periodontal tissues
∴ (Over-low & Over-high) (intrinsic immune & inflammatory response)
← which mediated by TLRs (← Toll-like receptors)
→ can lead to more lasting destruction (← of periodontal tissues)
❗: How various cytopathic factors
← of 1⃣ Pg. mediate inflammation 2⃣ immune response
← between the host through TLRs
→ to help precisely 1⃣ prevent 2⃣ diagnose 3⃣ treat → periodontitis in clinic
Introduction
Periodontitis
→ inflammatory pathological damage ← of 1⃣ the gums 2⃣ periodontal support tissues
← including 1⃣ the gums 2⃣ alveolar bone 3⃣ periodontal ligament 4⃣ cementum
The factor (initiating periodontitis)
→ is bioflim plaques
Red complex
← categorized together with 1⃣ Tf. 2⃣ Td.
→ has been irrefutably shown → to be the key pathogen
← which underlying the pathogenesis (← of chromic periodontitis)
(Host inflammatory & Immune responses)
← to microbial communities
→ change the sub-gingival environment
→ causing low-abundant key opportunistic pathogens → to become the dominant bacteria ← in the bioflim
→ ∴ Breaking the homeostatis (← between 1⃣ symbiotic micro-organisms 2⃣ the host) → promoting the development of periodontitis
Pg.
→ can also colonized some distant organs
← e.g. 1⃣ coronary artery 2⃣ palcenta 3⃣ liver 4⃣ brain
→ causing specific infections ← associated with the activation of TLRs
- Colonization in the host
- Immune escape
- Immuno-suppression
- Cellular entry and exit
- Extraction of nutrient from the host
- Release of virulence factors
Pg.
→ can produce various virulence factors
→ 1⃣ to evade the host immune defense system 2⃣ to destroy host periodontal tissues
The progression (← of periodontitis)
→ is regulated
← by mainly the interaction ← between 1⃣ the host immune response 2⃣ periodontal pathogens
∵ The indirect damage
← which caused by 1⃣ host congenital 2⃣ adaptive immunological responses
→ (low reactivity & hyper-responsiveness) (← of the immune response results)
← in persistent periodontal tissue damage
Innate immune response
→ to resist pathogenic microbial invasion
← which is also a prerequisite ← for adaptive immunity
Typical pathogenic molecules
→ are identified ← by multiple cell surface receptors
∴ Stimulating 1⃣ the expression of inducible co-stimulators 2⃣ releasing inflammatory factors & chemotatic factors & interferons
The key point ← in the innate immune response
← during the pathogenesis of periodontitis
→ lies in the recognition ← between 1⃣ pathogenic factors 2⃣ PRRs
Effect of LPS on Pg. Virulence
Heterogeneity of LPS
Pg.-LPS
← which is located on the lateral lobule (← of bacterial adventitia)
→ is a bacterial endotoxin ← which composed of 1⃣ lipid A 2⃣ core oligo-saccharide 3⃣ O-specific poly-saccharide
Pg.-LPS
→ is released after → the lysis of bacteria
→ is as free vesicles → outward from the outer membranes (← of living bacteria)
These LPS-containing micro-vesicles
← perpetuate the invasiveness of Pg.
→ giving it the ability → to destroy periodontal tissues and trigger inflammation
(TLR4 & TLR2)
→ can be simultaneously activated
← after recognition of Pg.-LPS
Ec.-LPS
→ can activate only TLR4
∴ The heterogeneous from (← of Pg.-LPS)
→ is identified as a PAMP
→ its regulatory role ← associated with host cell-specific TLRs → has been extensively studied
Recognition and Transportation of LPS via LBP-CD14-MD-2/TLR4
The combination of ← 1⃣ LPS 2⃣ MD-2/TLR4 complex
→ triggers → the host innate immune response
→ induces 1⃣ inflammation 2⃣ cytokine production
→ activates 1⃣ effector cells 2⃣ complementary systems
TLR4 is unique
∵ TLR4 must form → a dimer complex ← with MD-2
→ to capture its ligand LPS
The LPS poly-acyl chains
→ must be protected
← until they are incorporated ← into the MD-2/TLR4 complex
∵ Multiple acyl chains (← of LPS lipid A) → are key to the MD-2/TLR4 complex
LBP
← LPS-binding protein
→ is a 60 kDa serum glycoprotein
→ is mainly produced ← by 1⃣ hepatocytes 2⃣ lung 3⃣ gastrointestinal epithelial cells
A high concentration (← of LBP)
→ inhibits inflammation ← induced by LPS → to some extent
Low concentration (← of LBP)
→ has a high affinity for lipid A
∴ promote → formation of the LBP-LPS complex
LBP expression
← in gingival epithelial cells ← of the gingival-dental junction
→ is significantly lower ↓
← in chronic periodontitis patients ← than in healthy people
Both (LPB & exogenous sCD14)
→ could promote → the internalization of TLR4
❗: the concentration (← of sCD14 required) → was higher than that of LBP
TLRs
← as type I transmembrane proteins
→ are composed of 1⃣ a transmembrane structure 2⃣ an extra-cellular amino terminus domain 3⃣ and intra-cellular TIR homology domain
Some adaptor protein molecules
→ recognize the TIR domain
← including myeloid differentiation factor-88
TLR active pathways
→ are divided into 1⃣ MyD88-dependent 2⃣ TRIF-dependent pathways
∵ according to ← the adaptor protein recruited
∴ both (MD-1/CD180 & MD-2/TLR4)
→ are cell surface receptors
← that mediated LPS signaling pathways
← that have similar structure, but opposite functions
Different Lipid a Structures of Pg.-LPS Trigger Different Signal pathways
The mediation (← of TLR2)
→ is essential → for the loss of alveolar bone
← which caused by Pg. ← in animal model
Treatment (← of Ec.-LPS-tolerant bone marrow-derived macrophages)
← with Pg.
→ resulted in 1⃣ up-regulation of TLR2 expression 2⃣ excessive tumor necrosis factor production
Pg.-LPS reduced
→ the osteogenic polarization potential of PDLSCs ← via the TLR4-NF-κB signaling pathway
Blocking ← either (TLR4 & NF-κB) signaling
→ hindered LPS-induced alveolar bone loss
Both (Pg.-LPS and Ec.-LPS)
→ elevate the expression of the LBP protein
→ through TLR4 ← in human oral keratinocytes
Pg.-LPS
→ is achieved ← via (NF-κB & p38/MPAK pathways)
Ec.-LPS
→ is controlled ← by 1⃣ NF-κB 2⃣ p38/MPAK 3⃣ JNK signaling pathways
Pg.-LPS
→ enhanced → IL-6 mRNA expression
→ down-regulated → the cell surface molecules (TLR2 & TLR4)
Differences ← between (Pg.-LPS & Ec.-LPS)
→ based on (cell types & their exact molecular biological activities)
Pg.-LPS
→ up-regulated TLR4 expression ← in human gingival fibroblast
← with positive correlations of (dose & time)
→ induced → the expression of TLR2
Signaling pathways
← which triggered by Pg-LPS
→ are closely related to (its acylated lipid A isomer & target cells)
Pg.-LPS
→ can block the expression of ELAM-1
← induced by Ec.-LPS ← on human endothelial cells
The shared (MD-2 & MD-1) protein module
→ mediates → diverse biological functions → through specific interactions with lipid structures
The LPS-originating pathway
→ can be restricted ← by MD-1/CD180 ← which acting as an MD-2/TLR4 antagonist
∵ The common (features & functional) inter-relationship (← of MD-1/CD180 & TLR4/MD-2)
This antagonistic activity
→ results from the combination of the TLR4SV1 splicing variant binding with MD-2
→ resulting in the absence of signaling molecules
← in the extra-cellular N-terminal domain
The expression levels
← of both (CD180 & MD-1)
→ were significantly increased → after LPS bound LBP
Either (Pg.-LPS)
→ serves as → an excitomotor
The response to Pg.-LPS
→ varied considerably depending on
← 1⃣ the cell types examined 2⃣ the type of LPS produced
Both (LPS-1690 & LPS-1435/1449)
→ were effective stimulators (← of inflammation)
LPS-1435/1449
→ was more effective ← than LPS-1690
→ was less harmful ← than Ec.-LPS
← at the site of inoculation
Effect of gingipains on Pg. virulence
Classification of Gingipains
Gingipains
← named after Pg. clostripain
→ belonging to the cysteine protease family
→ existing in the outer 1⃣ membrane 2⃣ vesicles 3⃣ extra-cellular structure ← of Pg.
→ are important virulence factors ← which exert the vital function (← of mediating the interactions) ← between 1⃣ Pg. 2⃣ hosts
Gingipains
→ can be divided → into two categories
→ 1⃣ arginine-dependent gingipain R (Rgp) 2⃣ lysine-dependent gingipain K (Kgp)
Rgp
→ has been sub-divided into
→ 1⃣ RgpA 2⃣ RgpB
← on the basis of structure
These enzymes
→ are primarily compose of → the following components
→ 1⃣ a signal peptide 2⃣ N-terminal domain 3⃣ a catalytic domain (CD) 4⃣ immunoglobulin superfamily-like domain 5⃣ hemagglutinin/adhesion domain 6⃣ C-terminal domain
The CDs of (RgpB & RgpA)
→ are highly homologous
NO ❌ proteins
← with CD structures ← similar to those of Kgp
→ have been reported
Dimerization (← of the pro-domain)
→ plays a substantial role
← in the specific latency mechanism of Kgp
Secretion and Activation of Gingipains
Gingipains
→ are present ← in the form of an inactive zymogen
→ to block the unwanted proteolytic activity inside the cell
← when gingipains have just been translated
Acetylated-lysine residues
→ were found ← in the structures of these 3 mature proteases
→ suggesting that → acetylation is a potential mechanism ← underlying gingipain (activation & maturation)
PG1842
→ can acts as an acetyl-transferase
→ to replace Vim A ← in the process of RgpB acetylation
Contribution of Gingipains to Pathogenic Polymicrobial Bioflims
Gingipain protease activity
→ affects → the composition (← of multi-microbial bioflim) ← (quantitatively & qualitatively)
Gingipains
→ is also function as ligands
← in the co-aggregation ← of 1⃣ Pg. 2⃣ other oral bacteria
→ to promote → the colonization of Pg. ← in dental plaque
The most prominent outcome ← of replacing the normal strain
←with a Pg. Rgp/Kgp mutant
→ was the change in the Td. 3-D distribution → throughout the bioflim
This synergistic effect
→ was shown to be beneficial
→ 1⃣ the (survival & virulence) ← of bioflim colonies 2⃣ their ability to form → the red bacterial complex
Proteolytic Action of Gingipains in the Host TLR-Mediated Immune Response
Pg.
→ (cleaves & degrades) → a variety of host proteins
→ to escape immune defense
← including 1⃣ immuno-modulatory proteins 2⃣ signaling pathway regulatory proteins 3⃣ adhesion molecules
Pg.
→ can also recognize NLRs
← in 1⃣ a gingipain-independent manner 2⃣ activate NLR pyrin domain-containing 3-modified inflammatory corpuscle
→ release the inflammatory factors ← 1⃣ IL-1β 2⃣ TNF-α
Gingipains
← released by Pg. itself
→ can degrade mature 1⃣ IL-1β 2⃣ TNF-α
→ weakening the inflammatory response of the hots → to some extent
Gingipains
→ inhibit the cellular PI3K/Akt signaling pathway
← by cleaving extra-cellular PI3Kp85α-associated membrane proteins
→ achieving immune regulation of GECs
The weakening (← of CD14 efficacy)
→ is beneficial
→ 1⃣ the reproduction of eosinophilic bacteria ← in bacterial bioflims
→ 2⃣ leads to more severe chronic inflammation
Pg.
→ withstands → the bactericidal lytic activity ← in blood serum
∵ gingipains → are the main force ← in combating complement systems
The initial stages ← of these pathways
→ differ
The final outcomes
→ involve → the insertion of (membrane attack complexes) → into cell membranes
→ inducing → the generation of (chemicals & phagocytosis) ← of targeted Gram-negative bacteria
Facilitat ing Pg. infection
← via a C5a-mediated pathway
∵ gingipains induce → the polarization of M1 macrophages as a regulatory factor
C5a
→ is an effective chemotactic agent
→ is phagocyte activator ← which is unfavorable ← for Pg.
Pg.
→ has some resistance → to complement dissolution
∵ the anionic poly-saccharide structure (← of lipid A anchored) ← on the surface
Mechanisms
← of combined between 1⃣ C5aR ← the C5a receptor 2⃣ TLR2
← in macrophage
→ to promote the adaptability (← of Pg.)
C5a-C5aR synergistically
→ enhances → the weak cAMP response
← which activated by TLR2/TLR1 alone ← by stimulating calcium-dependent intracellular signaling
∴ A large amount of cAMP
The continuous increase (← of cAMP)
→ activates → cAMP-dependent protein kinase A ← PKA
→ destroys → the bactericidal function of iNOS (← inducible NO synthase)
The regulatory action (← of the cAMP/PKA pathway) ← on cell activity
← depends on mainly ← the binding of phosphorylate CREB (← cAMP response element binding protein)
Transpeptidation Function of Gingipains
Gingipains
→ have an undeniable transpeptidation effect
← which results from the transfer (← of several amino acids) ← between peptide chains
Pg.
← an obligate anaerobic bacterium ← which located in sub-gingival plaque
→ utilizes the trans-peptidase activity of gingipains
→ to extract → the required nutrients ← from human hemoglobin
Effect of Fimbriae/Pili on Pg. virulence
Structure and Genotype of Pili
Pili
→ are filamentous structure ← which located on the Pg. surface
→ that 1⃣ enhance the bacterial adhesion → to multiple types of surfaces 2⃣ take part in the formation of biofilm
Pg. pili
→ can be exhibited ← in at least two forms
→ 1⃣ the major FimA 2⃣ the minor Mfa
The major proteins
→ are encoded ← by fimA gene
The minor subunits
→ are composed of mainly (Mfa1 structural subunit proteins)
The fimA genotype II and IV
→ are widely distributed ← in periodontitis isolates
Role of Fimbriae/Pili in TLR-Mediated Host Immune Response
Adhesion
→ is an indispensable process
← in the pathological development of periodontitis
∵ The pili are the most prominent structure ← on the surface of bacteria
Pili
→ can mediate → the attachment of Pg.
→ to 1⃣ hydroxyapatite 2⃣ hGF 3⃣ epithelia
Pg. long fimbrial proteins
→ were capable of activating human GECs
← through TLR2 ← with a complex of (sCD14 & LBP)
→ up-regulating IL-8 expression and NF-κB activation
The 67-kDa minor pili
← on the Pg. surface
→ stimulated the expression of 1⃣ TNF-α 2⃣ IL-1α 3⃣ IL-1β 4⃣ IL-6 cytokine
← via the TLR2/complement receptor3 pathway
∴ 1⃣ the vital function of regulating immunity 2⃣ mediating tissue damaging
← during the development of periodontitis
The different combinations
← between 1⃣ the co-receptor 2⃣ TLR2
→ directly affect → the activation of microbial molecules and TLR2
The combination (← of 1⃣ pili 2⃣ CXCR4)
→ blocks ↓ → the production of TNF-α (← which mediated by NF-κB activation)
→ promotes ↑ IL-10 production
The key factor ← of this mechanism
→ is → cAMP-dependent PKA → inhibits the MyD88-dependent anti-bacterial pathway
← induced by TLR2 activation
TLR2-MyD88
→ is a classical inflammatory pathway
← which mediates the periodontal tissue destruction ← caused by Pg.
Activation (← of the TLR2-PI3K signal)
→ caused neutrophils
→ to produce the pro-inflammatory cytokine TNF-α
∴ Inhibiting → 1⃣ the maturation of phagosome 2⃣ prolonging survival time
Conclusion
The oral cavity
→ is an open micro-ecological environment
← with more than 700 species of micro-organisms
← which normally maintain → a dynamic balance ← with the host's immune system
Periodontitis
← caused by periodontal pathogens
→ which destroys → the epithelial junction ← between 1⃣ the teeth 2⃣ periodontal tissue
Pg.
→ can directly destroy → periodontal tissues
← by secreting toxic factors
← e.g. 1⃣ LPS 2⃣ gingipains 3⃣ pili
Pg.
→ trigger host defense cells
→ regulate the microbial-host immune-inflammatory response