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Mitogen-Activated Protein Kinase 2 Signaling Shapes Macrophage Plasticity in Aggregatibacter
Bethany A Herbert1, Heidi M Steinkamp1, Matthias Gaestel2
1Department of Oral Health Sciences and the Center for Oral Health Research, Medical University of South Carolina, Charleston, South Carolina, USA.
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+/+ and Mk2-/- 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-/- mice compared to Mk2+/+ 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.
Insights
MAPK-activated protein kinase 2 (MK2) signaling in macrophages regulates chemokine production during Aggregatibacter actinomycetemcomitans infection. MK2 deficiency reduces inflammation and bone loss associated with aggressive periodontal disease.
Area of Science:
- Periodontal disease pathogenesis
- Innate immune response
- Skeletal biology
Background:
- Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) drives aggressive periodontal disease and alveolar bone loss.
- A. actinomycetemcomitans activates p38 MAPK and MK2 stress pathways in macrophages, influencing host responses.
- Chemokines are upregulated during periodontal inflammation to recruit immune cells.
Purpose of the Study:
- To investigate the role of MK2 signaling in regulating chemokine production during A. actinomycetemcomitans pathogenesis.
- To understand MK2's contribution to inflammation-driven bone loss in periodontal disease.
Main Methods:
- Murine calvarial and chimeric air pouch models were used to study A. actinomycetemcomitans infection.
- Gene expression analysis (RNA) of macrophage markers and chemokines (CCL3, CCL4) was performed.
- Micro-computed tomography (micro-CT) assessed bone resorption and osteoclast formation.
Main Results:
- MK2 positively regulated macrophage-associated RNA (Emr1, Itgam, Csf1r, Itgal, Tnf, Nos2).
- MK2 signaling modulated CCL3 and CCL4 chemokine expression in calvarial tissue and differentially in hematopoietic/nonhematopoietic compartments.
- Mk2-deficient mice exhibited reduced bone resorption and osteoclast formation compared to wild-type mice.
Conclusions:
- MK2 signaling in macrophages plays a significant role in regulating chemokine responses during A. actinomycetemcomitans infection.
- MK2 contributes to inflammation and subsequent alveolar bone loss in aggressive periodontal disease.
- Targeting MK2 may offer a therapeutic strategy for periodontal disease treatment.
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