CXCR4 signaling in macrophages contributes to periodontal mechanical hypersensitivity inPorphyromonas gingivalis-induced periodontitis in mice

Abstract

BackgroundPeriodontitis is an inflammatory disease accompanied by alveolar bone loss and progressive inflammation without pain. However, the potential contributors eliminating pain associated with gingival inflammation are unknown.Resultswe examined the involvement of CXC chemokine receptor type 4 (CXCR4) on the mechanical sensitivity of inflamed periodontal tissue, using a mouse model of periodontitis established by the ligation of the tooth cervix of a maxillary second molar and inoculation with Porphyromonas gingivalis (P. gingivalis). Infiltration of inflammatory cells into gingival tissue was not observed following the inoculation. Under light anesthesia, the mechanical head withdrawal threshold (MHWT) on the buccal gingiva was measured using an electronic von Frey anesthesiometer. No significant changes in MHWT were observed in the mice with P. gingivalis-induced periodontitis during the experimental period. Continuous administration of CXCR4 neutralizing antibody to the gingival tissue significantly decreased MHWT and increased the number of gingival CXCR4 immunoreactive macrophages in the periodontitis group. Nitric oxide metabolites in the gingival tissue were significantly increased after the inoculation of P. gingivalis and were reduced by gingival CXCR4 neutralization. Gingival L-arginine administration induced gingival mechanical allodynia in naive animals. Moreover, the decrease in MHWT after treatment with P. gingivalis and CXCR4 neutralization was partially reversed by nitric oxide synthase inhibition in the gingival tissue. Nuclear factor-kappa B was expressed in infiltrating macrophages after inoculation of P. gingivalis and administration of the nuclear factor-kappa B activator betulinic acid induced gingival mechanical allodynia in naive mice.ConclusionsThese findings suggest that CXCR4 signaling inhibits nitric oxide release from infiltrating macrophages and is involved in modulation of the mechanical sensitivity in the periodontal tissue in P. gingivalis-induced periodontitis.

Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events

“…6h ). Top pathways included CXCR4 signaling, involved in cell migration and TLR2 signaling 93,94 , which indicates pro-inflammatory functions of these cells. We also identified pathways involved in podosome formation (RAC1 95,96 ), and phagocytosis (RAC1 97 and IL-21 98 signaling), both processes that promote reparative functions in macrophages.…”

TET1 Knockdown Inhibits Porphyromonas gingivalis LPS/IFN-γ-Induced M1 Macrophage Polarization through the NF-κB Pathway in THP-1 Cells

“…Periodontitis is an inflammatory disease caused by infection with periodontal pathogens such as Pg., which results in tissue destruction in the periodontal tissue accompanied by extensive macrophage infiltration [29,30,31]. Macrophages are heterogeneous and plastic cells that can be polarized into different phenotypes and exhibit various functions in response to surrounding stimuli [32].…”

“…Pg. LPS can induce the NF-κB signaling pathway activation to generate M1-related cytokines such as IL-6, TNF-α, IL-1β, and nitric oxide (NO) in macrophages during the progression of periodontitis [30,37]. In a mouse periodontitis model established by exposure to Pg., human β-defensin 3 (hBD3) reduces M1 macrophage polarization by inhibiting the phosphorylation of the NF-κB p65 subunit, which results in less alveolar bone loss [38].…”

Increased Anxiety-Like Behavior in the Acute Phase of a Preclinical Model of Periodontal Disease

“…We observed increased anxiety-like behaviors in active-PD animals of the Acute phase when comparing to sham-PD animals of the same group and a positive association between anxiety and mechanical allodynia of the affected orofacial region. Although mechanical allodynia is commonly observed in patients with different stages of periodontitis ( 40 , 41 ), preclinical models of periodontitis show discordant results ( 42 , 43 ). These discrepancies may be due to the technique employed to assess the mechanical allodynia threshold (e.g., sedated vs. awake animals) and the murine model used (e.g., mouse vs. rat).…”