Cell-Type-Specific ROS-AKT/mTOR-Autophagy Interplay-Should It Be Addressed in Periimplantitis?

Abstract

Periimplantitis represents an inflammatory disease of the soft and hard tissues surrounding the osseointegrated dental implant, triggering progressive damage to the alveolar bone. Cumulative data have revealed that periimplantitis plays a crucial part in implant failure. Due to the strategic roles of autophagy and its upstream coordinator, the AKT/mTOR pathway, in inflammatory responses, the crosstalk between them in the context of periimplantitis should become a key research target, as it opens up an area of interesting data with clinical significance. Therefore, in this article, we aimed to briefly review the existing data concerning the complex roles played by ROS in the interplay between the AKT/mTOR signaling pathway and autophagy in periimplantitis, in each of the main cell types involved in periimplantitis pathogenesis and evolution. Knowing how to modulate specifically the autophagic machinery in each of the cellular types involved in the healing and osseointegration steps post implant surgery can help the clinician to make the most appropriate post-surgery decisions. These decisions might be crucial in order to prevent the occurrence of periimplantitis and ensure the proper conditions for effective osseointegration, depending on patients' clinical particularities.

Keywords: ROS; autophagy; autophagy modulators; dendritic cells; gingival fibroblasts; macrophages; osteoblasts; osteocytes; periimplantitis.

Figure 1

Proposed schematic representation of the ROS–AKT/mTOR–autophagy interplay. In moderate-ROS-level conditions, AKT is involved in the activation of the mTORC1 complex, which in turn inactivates the ULK complex, vital for autophagic flux activation. Moreover, AKT is able to downregulate the activity of FOXO transcription factors as a means to prevent autophagy activation. mTORC1 activity triggers ROS accumulation and ATP level decrement, finally leading to its feedback inhibition via AMPK. On the contrary, under high cellular ROS levels, autophagy and/or apoptosis is upregulated via Beclin 1 activation [70,71,72,73,74,75,76,77,78,79].

Figure 2

Schematic representation of macrophage polarization trend, mediated by interleukines [113,114,115,116].

Figure 3

Schematic representation of the interplay between the PI3K/AKT/mTOR pathway, autophagy and M1/M2 polarization. The PI3K/AKT/mTOR pathway integrates molecular signals from several receptors, including cytokine (such as IL-2 family) receptors. The AKT pathway converges metabolic and inflammatory signals to regulate their responses via modulating MPH functional polarization [102].

Figure 4

Roles of autophagy in OCs. OB-secreted and osteocyte-secreted RANKL binds to its receptor RANK on OCs, leading to Beclin-1 upregulation. Upregulated Beclin-1 triggers the increment of Atg5/7/12 levels and, consequently, the enhanced conversion of LC3I to LC3II. RANKL-RANK upregulates the Nox4 level, increasing the nonmitochondrial ROS level. Consequently, the PERK/eIF-2α/ATF4 pathway is activated, leading to autophagy stimulation. The activated autophagic machinery consequently upregulates the expression of OCs’ genes (TRAP and CTSK (Cathepsin K)), ruffled border and podosome organization, and bone resorption, by stimulating the release of CTSK and MMP9 [186,187,188,189,190,191,192,193,194,195,196].

Figure 5

Proposed scheme of cell-type-specific autophagy modulation in order to promote osseointegration and prevent periimplantitis occurrence. Am—autophagy modulators; M1—M1 MPH phenotype; M2—M2 MPH phenotype.