Mitogen-Activated Protein Kinase 2 Signaling Shapes Macrophage Plasticity in Aggregatibacter actinomycetemcomitans-Induced Bone Loss

Abstract

Aggregatibacter actinomycetemcomitans is associated with aggressive periodontal disease, which is characterized by inflammation-driven alveolar bone loss. A. actinomycetemcomitans activates the p38 mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase 2 (MK2) stress pathways in macrophages that are involved in host responses. During the inflammatory process in periodontal disease, chemokines are upregulated to promote recruitment of inflammatory cells. The objective of this study was to determine the role of MK2 signaling in chemokine regulation during A. actinomycetemcomitans pathogenesis. Utilizing a murine calvarial model, Mk2 ϩ/ϩ and Mk2 Ϫ/Ϫ mice were treated with live A. actinomycetemcomitans bacteria at the midsagittal suture. MK2 positively regulated the following macrophage RNA: Emr1 (F4/80), Itgam (CD11b), Csf1r (M-CSF Receptor), Itgal (CD11a), Tnf, and Nos2. Additionally, RNA analysis revealed that MK2 signaling regulated chemokines CCL3 and CCL4 in murine calvarial tissue. Utilizing the chimeric murine air pouch model, MK2 signaling differentially regulated CCL3 and CCL4 in the hematopoietic and nonhematopoietic compartments. Bone resorption pits in calvaria, observed by micro-computed tomography, and osteoclast formation were decreased in Mk2 Ϫ/Ϫ mice compared to Mk2 ϩ/ϩ mice after A. actinomycetemcomitans treatment. In conclusion, these data suggest that MK2 in macrophages contributes to regulation of chemokine signaling during A. actinomycetemcomitans-induced inflammation and bone loss.

Inhibition of the histone demethylase KDM4B leads to activation of KDM1A, attenuates bacterial-induced pro-inflammatory cytokine release, and reduces osteoclastogenesis

“…An increase in resorption pits due to osteoclast activity was observed in calvariae treated with A.a, confirming this as a viable model for periodontal disease [33]. Staining for tartrate resistant acid phosphatase (TRAP) and F4/80 marked the area in the calvarial sections most active with inflammatory infiltration.…”

“…To determine whether KDM4B inhibition could be used as a therapeutic strategy to manage periodontal disease, we first demonstrated that the abundance of KDM4B protein is significantly increased in areas of inflammatory infiltrate marked by increased F4/80+ macrophage cells and increased tartrate resistant acid phosphatase (TRAP)+ osteoclastic cells following live A.a. subcutaneous injection into murine calvariae (Figure 1(a)) [36]. The murine genome does not express KDM4E [37], leading us to believe that the ML324-induced immunomodulatory effect is entirely dependent on KDM4B.…”

“…Calvariae from mice with periodontal disease, collected as previously described [33] were formalin fixed, decalcified using 0.5 M EDTA, pH 8.0 for 2 weeks, paraffin embedded and cut into 7 μm sections following standard protocols. Human periodontal tissues were formalin fixed, paraffin embedded and cut into 7 μm sections following standard protocols.…”

Integrated analysis of long noncoding RNA‐associated competing endogenous RNA network in periodontitis

“…The activation of nuclear β‐catenin can inhibit the noncanonical Wnt pathway, leading to increased proliferation but reduced osteogenic differentiation of periodontal ligament stem cells . ITGAL (Integrin Subunit Alpha L, also known as LFA‐1A, CD11A; gene ID: 3683) was shown to be upregulated in periodontitis and encoded the integrin α L chain of the integrin lymphocyte function‐associated antigen‐1 (LFA‐1/CD11a). LFA‐1/CD11a, a key immunoregulatory cytokine, has been suggested to play an important role in the pathogenesis of periodontal disease, possibly by T‐cell recruitment and retention in the gingival tissue .…”

The in vivo T helper type 17 and regulatory T cell immune responses to Aggregatibacter actinomycetemcomitans

“…Aggregatibacter actinomycetemcomitans oral infection, in association with periodontal disease, can also lead to bone loss due to the inflammatory process. Recently, it has been shown that A. actinomycetemcomitans infection activates stress pathways in macrophages and upregulates chemokine signaling during inflammation and osteoclastogenesis . Despite recent evidence regarding A. actinomycetemcomitans ‐induced bone loss and proinflammatory mechanisms, there is still limited information on A. actinomycetemcomitans invasion and its systemic pathogenesis.…”