Elevated CD14 (Cluster of Differentiation 14) and Toll-Like Receptor (TLR) 4 Signaling Deteriorate Periapical Inflammation in TLR2 Deficient Mice.
Apical periodontitis (periapical lesions) is an infection-induced chronic inflammation in the jaw, ultimately resulting in the destruction of apical periodontal tissue. Toll-like receptors (TLRs) are prominent in the initial recognition of pathogens. Our previous study showed that TLR4 signaling is proinflammatory in periapical lesions induced by a polymicrobial endodontic infection. In contrast, the functional role of TLR2 in regulation of periapical tissue destruction is still not fully understood. Using TLR2 deficient (KO), TLR2/TLR4 double deficient (dKO), and wild-type (WT) mice, we demonstrate that TLR2 KO mice are highly responsive to polymicrobial infection-induced periapical lesion caused by over activation of TLR4 signal transduction pathway that resulted in elevation of NF-kB (nuclear factor kappa B) and proinflammatory cytokine production. The altered TLR4 signaling is caused by TLR2 deficiency-dependent elevation of CD14 (cluster of differentiation 14), which is a co-receptor of TLR4. Indeed, neutralization of CD14 strikingly suppresses TLR2 deficiency-dependent inflammation and tissue destruction in vitro and in vivo. Our findings suggest that a network of TLR2, TLR4, and CD14 is a key factor in regulation of polymicrobial dentoalveolar infection and subsequent tissue destruction. Anat Rec, 299:1281-1292, 2016. © 2016 Wiley Periodicals, Inc.
Department of Immunology and Infectious Diseases, the Forsyth Institute, Cambridge, Massachusetts.
Daniel
D
Rider
Department of Oral and Maxillofacial Pathobiology, Hiroshima University, Japan.
Hisako
H
Furusho
Department of Immunology and Infectious Diseases, the Forsyth Institute, Cambridge, Massachusetts.
Shuang
S
Xu
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
Alexander J
AJ
Trachtenberg
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
Winston Patrick
WP
Kuo
Department of Immunology and Infectious Diseases, the Forsyth Institute, Cambridge, Massachusetts.
Kimito
K
Hirai
Department of Periodontology and Endodontology, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan.
Mako
M
Susa
Department of Endodontics, Faculty of Dentistry, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
Laila
L
Bahammam
Department of Immunology and Infectious Diseases, the Forsyth Institute, Cambridge, Massachusetts.|Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts.
Philip
P
Stashenko
Division of Functional Morphology, Department of Anatomy, Iwate Medical University, Morioka, Iwate, 020-8505, Japan.
Akira
A
Fujimura
Department of Immunology and Infectious Diseases, the Forsyth Institute, Cambridge, Massachusetts.|Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts.
Hajime
H
Sasaki
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010518:Periodontitis / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
CD14; apical periodontitis; inflammation; innate immunity; toll-like receptor (TLR)