The skeletal and immune systems are two functionally interconnected organizational units that affect each other by sharing multiple cells and mediators, such as cytokines, receptors and other signaling molecules. A prominent example of this interplay is the orthodontic tooth movement (OTM) [1], in which a complex and highly coordinated non-infectious inflammation of periodontal tissues is an essential pre-requisite [2]. The inflammatory processes are induced by applying orthodontic forces, generating compression and tension areas within the periodontal ligament (PDL) [3, 4]. Blood vessel and nerve endings occlusion and hypoxia trigger periodontal vasodilation and the extravasation of various immune cells [2, 4]. Among other tissue-resident cells, immune cells, such as neutrophiles, macrophages, T and B lymphocytes, may contribute to increased levels of various immune factors in the periodontium, such as various chemokines, growth factors, cytokines [e.g., interleukin-(IL)-1β, IL-6, IL-8, tumor necrosis factor-(TNF)-α, interferon-(IFN)-γ], and prostaglandin E₂ (PGE₂). All these inflammatory mediators contribute to the regulation of osteoclast- and osteogenesis and the activities of bone remodeling cells (osteoclasts and osteoblasts) [1, 5]. Hence, the inflammatory environment is directly involved in orchestrating the interconnected catabolic (bone resorption) and anabolic (bone formation) processes within the periodontium, which finally leads to alveolar bone turnover and tooth movement [6]. In 1962, Burstone [7] divided OTM into three different phases, depending on the tooth displacement rate. More recently, this model was updated, proposing four distinct OTM phases (initial phase, lag phase, acceleration phase and linear phase). The initial phase is induced immediately after applying orthodontic forces and lasts between 24 and 48 h. It is characterized by an instantaneous tooth displacement within the alveolar socket. Due to emerging necrosis and hyalinization of the PDL and the adjacent tissue, the initial phase is followed by the lag phase exhibiting low or even no tooth displacement. The lag phase persists for 20–30 days. After necrotic and hyalinized tissue is completely cleared by osteoclasts and phagocytes during a process called undermining resorption, tooth displacement rate starts to increase gradually, turning into a continuous rate of tooth movement during the linear phase (rapid OTM) as long as mechanical stimuli persist [8–10].

Apart from immune cells, it is well established that the cellular component of the PDL functions as primary mechanosensors, translating mechanical stimuli into biological signals [11, 12]. The cells in the PDL are a heterogeneous population with a fibroblast-like morphology containing endothelial, neuronal and epithelial cells, osteoblasts, fibroblasts and mesenchymal stem/stromal cells (MSCs) [13, 14], exhibiting progenitor and self-renewing potentials [14–16]. Plenty of studies on OTM used the whole heterogeneous cell bulk from the PDL, naming them as PDL cells or PDL fibroblasts [5]. There are also studies, terming them periodontal ligament stem cells (hPDLSCs), although comparable isolation methods were used (e.g., [17–22]). Additionally, these studies mainly verify the stemness of isolated cells in accordance with the minimal criteria for MSCs as settled by the International Society for Cell and Gene Therapy (ISCT) [15]: plastic adherence in vitro, expression of specific surface markers and tri-lineage differentiation potential in vitro. Due to uniformity, we will name the cells isolated from the PDL as hPDLSCs throughout the whole article. As primary mechanosensors within the PDL, hPDLSCs contribute to the force-induced alveolar bone and PDL remodeling and consequently to OTM via multiple different ways (reviewed in Li et al. [5] and Huang et al. [11]). Orthodontic forces change the proliferation and osteogenic differentiation capacity of hPDLSCs. They directly affect osteoclast- and osteogenesis via the production of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). hPDLSCs produce multiple other regulatory molecules, establishing a signaling axis between them and osteoblasts, osteoclasts and osteocytes. They also secrete anabolic as well as catabolic molecules, involved in remodeling the extracellular matrix (ECM) of the PDL during OTM [5, 11]. Furthermore, hPDLSCs appears to be the most important player in triggering mechanical forces-induced non-infectious inflammation via the secretion of various pro-inflammatory factors [3, 5, 23, 24]. Beside all these regulatory mechanisms, their well-defined immunomodulatory activities (reviewed in Andrukhov et al. [25]) have been neglected as possible regulators of OTM, so far. Hence, this perspective article will be restricted to the potential role of the cytokine-boosted immunomodulatory properties of hPDLSCs in the context of OTM. The role of other cellular processes involved in OTM, such as chemotaxis, homing and the role of damage-associated patterns will be out the scope of this article and are discussed elsewhere (e.g., [5]).

While the role of cytokine secretion by hPDLSCs in inducing non-infectious inflammation during OTM is well established, the involvement of different immune cells during OTM still needs extensive research [5]. Nevertheless, there are obvious hints that innate as well as adaptive immune cells are involved in the progress of aseptic inflammation during OTM, by secreting chemokines, pro- and anti-inflammatory cytokines and by contributing to vasodilation and necrotic tissue removal. However, the precise immunological mechanisms remain vague.

The inflammatory reactions during OTM are hypothesized to be highly dynamic and specific for each OTM phase (reviewed in Chaushu et al. [2]). The initial phase seems to be characterized by acute inflammatory reactions, involving typical innate immune responses from periodontal tissue-resident and extravasated immune cells and leading to high levels of various pro-inflammatory cytokines. During the further course of OTM, the authors claim that the induced inflammation seems to be resolved. However, this resolution appears incomplete, turning into a low-grade chronic inflammation. These low-grade chronic inflammatory processes may persist during the acceleration and linear phases until the force is renewed, which facilitates a new acute inflammatory reaction.

It is well explored that under inflammatory environment hPDLSCs are fundamental modulators of the local immune responses, affecting various immune cells, such as macrophages, granulocytes, dendritic cells, B and T lymphocytes [25]. hPDLSCs execute their immunomodulatory activities via various mechanisms, such as the expression of soluble (e.g., indoleamine-2,3-dioxygenase-1, prostaglandin E₂, tumor necrosis factor-inducible gene 6 protein) and membrane-bound (e.g., programmed cell death ligand-1/2) immunomediators. Since the immunomediator production get boosted by various cytokines, such as TNF-α, IL-1β, and IFN-γ [25–29], it may be possible that the aseptic inflammatory environment during OTM modulates the immunomodulatory properties of hPDLSCs, which, in turn, should affect immune cells' activity and inflammatory reaction (Figure 1). Additionally, recent studies have also demonstrated that MSCs' secreted extracellular vesicles are involved in the immunomodulatory crosstalk between MSCs and immune cells [30]. However, if and how far the aseptic inflammation may be also affected by these immunomodulatory mechanisms of hPDLSCs remains largely unknown. So far, only few recently published studies gave first clues that orthodontic forces may impact the immunomodulatory abilities of hPDLSCs [31–35].

Besides first hints that mechanical force-triggered hPDLSCs influence immune cells during OTM by their immunomodulatory activities [31–35], there are several other facts that allow the assumption that immunomodulatory properties participate in regulating inflammatory processes during OTM. First, several immunomediators, such as IL-10 and TGF-β, which are secreted by hPDLSCs [25], are known to participate in OTM by inducing osteogenesis [69]. Second, the acute inflammatory phase during the initial OTM stage is characterized by a significant increase in various pro-inflammatory factors, such as IL-β, TNF-α, and IFN-γ [1]. These cytokines are also potent activators of paracrine and direct cell-to-cell immunomodulatory mechanisms of hPDLSCs. Moreover, certain cytokines or a combination of cytokines activate only specific immunomodulatory functions [25, 29], which may contribute to the fine-tuning of the aseptic inflammation during OTM.

Moreover, hPDLSCs adopt a pro- or anti-inflammatory phenotype in the presence of low or high cytokine levels, respectively [27]. Hence, we suggest a potential mechanism for how hPDLSCs are involved in regulating the initiation of acute inflammation and its transition to a low-grade chronic inflammation during OTM: (1) Immediately after applying orthodontic forces the combination of mechanical forces and low cytokine levels may facilitate the adaption of a pro-inflammatory phenotype of hPDLSCs with increased secretion of various cytokines [3, 5, 23, 24] and possible reduced activity of immunomodulatory mechanisms (C.B. and O.A., unpublished data). These together may facilitate immune cell recruitment and activation, contributing to the aseptic inflammatory environment during the initial OTM stage. (2) Subsequently, high cytokine level-triggered immunomodulatory activities of hPDLSCs may initiate an anti-inflammatory phenotype, contributing to the resolution of the inflammatory reaction in the further course of OTM. Dampening the cytokine-induced immunomodulatory mechanisms of hPDLSCs through applied orthodontic forces, however, to a level that is still higher compared to unstimulated hPDLSCs (C.B. and O.A., unpublished data), may contribute to the potential partial nature of the inflammatory resolution [2].

In conclusion, hPDLSCs are well-established key players in initiating non-infectious inflammation in the PDL during OTM. There are already first hints that orthodontic forces influence immunomodulatory mechanisms of hPDLSCs and hence the interaction between them and various immune cells [31–35]. hPDLSCs are highly potential candidates involved in orchestrating the timely-dynamic aseptic inflammatory reactions during OTM. In this regard, their mainly immunosuppressive immunomodulatory property [25] could be the secret player. It can affect the course of aseptic inflammation (Figure 1) as well as might also indirectly influence bone resorption through the modulation of OPG/RANKL production by immune cells [1]. Unfortunately, only a handful of studies have already examined the direct influence of orthodontic force-triggered hPDLSCs on various immune cells [31–35, 70]. How far immunomodulatory activities of hPDLSCs are involved in the initial stage of OTM and in transforming acute inflammation into a potential low-grade chronic inflammation [2] need further extensive research.

Future in vivo studies should investigate the involvement of various MSCs-dependent immunomodulatory mechanisms in OTM by trailing the levels of soluble immunomediators in the gingival crevicular fluid and saliva of OTM patients and by depleting them in different animal models. In vitro studies should explore the expression of various immunomediators in hPDLSCs and their effect on various immune cells in the context of OTM. These experiments should be performed using different types of co-culture models and various inflammatory environments. Since the response of hPDLSCs on mechanical forces depends on the force type and amplitude [71, 72], the effect of these factors must be considered.

Deciphering the involvement of hPDLSCs derived immunomodulation in OTM may also benefit orthodontic patients directly. The inflammatory component of OTM has an immense attention as a point of action for the pharmacological acceleration of orthodontic tooth displacement [2]. The immunomodulatory mechanisms of hPDLSCs may also function as a new contact point for accelerating OTM pharmacologically. Furthermore, over the years, the number of adults with orthodontic treatment has substantially increased. In this patient group, the incidence of periodontitis is significantly higher, which might negatively influence orthodontic treatment [73, 74], by triggering a periodontitis-associated dormant inflammation [73, 75]. It is already known that hPDLSCs from periodontitis patients exhibit reduced immunosuppressive activities (reviewed in Andrukhov et al. [25]). Unraveling the behavior of immunomodulatory potential of hPDLSCs during OTM may further shed light on the OTM-periodontitis interaction. Additionally, an undesirable side-effect of applying orthodontic forces is root resorption. Animal studies already demonstrated that MSCs inhibit orthodontically-induced root resorption (OIRR) and/or trigger reparative mechanisms. It is thought that this is achieved by the cementogenic differentiation potential of hPDLSCs [76–78]. If and how their immunomodulatory properties are mechanistically involved in OIRR needs further investigation.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

CB, ZZ, and OA contributed to the design of the work. CB wrote the original draft, which was edited by ZZ and OA. All authors approved the final version of the manuscript.

This research was funded by Austrian Science Fund (FWF); Grant Number P 35037 (to OA).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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