1.
Introduction
Mast cells (MCs) are myeloid tissue cells containing a large number of basophilic granules, known for their important role in the development of allergies, as well as in the regulation of the inflammatory process. MCs granules contain pre-stored mediators that are released in response to a stimulus, such as histamine, proteoglycans, or proteases [1]. Moreover, when stimulated, MCs begin to synthesize mediators de novo, such as various cytokines, chemokines, and growth factors [1]. It should be noted that MCs are characterized by a differential release of their mediators; depending on the stimulus, a different set of factors are synthesized and secreted by cells [1],[2]. Due to this and a unique set of mediators, mast cells are involved in all stages of inflammation, from its initiation to wound healing [3].
Osteoarthritis (OA) is a common cause of population disability. Regardless of the reasons for the disease initiation, whether it be trauma, aging, obesity or genetic causes, OA is largely inflammatory [4],[5]. The important signs of joint inflammation are infiltration by immune cells, the growth of catabolism enzymes and the synthesis of pro-inflammatory cytokines and chemokines [5],[6]. And a large role in the regulation of the inflammatory process belongs to MCs, which, due to the large spectrum of regulatory molecules and the presence of differential secretion, can “orchestrate” other cells [3].
In the joint, MCs are located in the subintima of the synovial membrane, capsule, and periarticular fat, and generally play a negative role in the development of OA [7]. Genetic and pharmacological depletion of MCs leads to a decrease in the severity of symptoms in experimental OA models [8]. Moreover, injection of MCs causes histopathological changes of OA in cartilage, although without pain and swelling [9]. Injection of MCs after the development of OA aggravates the disease, and this effect is leveled by the membrane stabilizer Tranilast [9].
With the development of OA, an increase in the number of both degranulated and intact MCs has been shown [7]. At the same time, there is a clear positive correlation between the amount of MCs and synovial inflammation, as well as pain assessed by the visual analog scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) scores [10]–[12]. It has also been noted that the number rather than the percentage of degranulated MCs correlates with pain and cartilage damage [11].
Recruitment of new MCs seems to occur due to the secretion of stem cell factor (SCF) by various synovial cells, including fibroblasts, monocyte/macrophages, and endothelial cells [13]. SCF binds to the c-kit receptor, which is present only on MCs in adulthood, causing progenitor division, maturation, and chemotaxis [13],[14]. Drugs targeting c-kit and MCs maturation such as Imatinib [8] and Sorafenib [15] have been shown to reduce experimental OA.
In osteophytes developing in OA, an increase in the number of MCs has been shown, mainly due to migration of the precursors from the bloodstream; however, recruitment from the subchondral bone is also possible, and the differentiation and maturation of MCs are largely provided by the components of synovial fluid [16]. Apparently, the environment that forms in osteoarthritis causes additional recruitment of MCs, which creates a vicious circle of inflammation.
Thus, a clear correlation between the MCs number, their morphological and functional status and the degree of OA development strongly suggests that MCs play a significant role in the pathogenesis of OA. Below we will consider in more detail which pathways of MCs activation and which of their mediators may be involved in this process. We also summarized which MCs-targeted pharmacological approaches have already shown some success in experimental or clinical studies and could already be used to treat OA.
2.
Mast cell activation
2.1. Immunoglobulin E (IgE)
IgE is widely known as an activator of MCs in immediate hypersensitivity (type I) allergic reaction. However, the role of IgE and its ability to activate MCs cannot be underestimated in OA. In a model of experimental OA, cartilage damage, osteophyte formation, and synovitis were significantly less expressed in IgE-deficient and anti-IgE neutralizing antibody recipient mice [8]. Pilot clinical trials in humans have shown the efficiency of anti-IgE therapy [17]. A similar effect has been detected in mice with a deficit of the IgE high-affinity receptor (FcϵRI) and in pharmacological inhibition of downstream signaling caused by the Syk agonist PRT062607 [8].
Activation of IgE receptors on MCs causes the calcium-dependent release of pre-stored mediators from granulae, which is reviewed hereinafter [8]. At the same time, phosphoinositide 3-kinases (PI3K), extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protein kinase C (PKC) are also activated, initiating the synthesis of mediators de novo, the first being metabolites of arachidonic acid, cytokines, chemokines, NO, and reactive oxygen species (ROS) [1],[18].
In spite of the great role of IgE in its pathogenesis, OA does not appear to be a typical allergic reaction, and the problem of antigen for immunoglobulin is still open. Some authors suppose that exogenous allergens or cartilage breakdown products may become antigens [8]. On the contrary, MCs activation mechanisms by IgE not bound with antigens have been described [19]. It is interesting that the general level of IgE (particularly Dermatophagoides farinae-specific IgE) in serum correlates with an increased risk of OA development [20], and allergy cases appear more often in patients with OA [21]. It seems that the presence of IgE, both free and bound with antigens, may increase OA development whilst not being its initiator.
2.2. Damage-associated molecular patterns (DAMPs)
The development of traumatic osteoarthritis occurs after trauma and tissue damage, and DAMPs that are released in damaged tissues play the main role in initiating this process [22]. DAMPs include components of destroyed extracellular matrices, high-mobility group box 1 protein (HMGB1), heat shock proteins (HSPs), uric acid, altered matrix proteins, and S100 proteins. DAMPs play an important part in the initiation and development of OA (for detail, see [23]). Briefly, activation of the receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLRs) causes the release of matrix metalloproteinases (MMPs), ROS, cytokines, and chemokines by innate immunity cells, which are present in the synovial membrane. This causes a further increase in the inflammatory response. There are different types of TLRs on the membrane of MCs, and their activation causes the de novo synthesis and secretion of cytokines, chemokines, and phospholipid metabolites [24]. It has been shown that extra domain A of fibronectin (FN-EDA), which is gained by protease-infused fibronectin breakdown, is a ligand for TLR4 and causes dose-dependent secretion of tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and IL-1β [25]. In experimental OA, an intra-articular injection of the inhibitor of TLR4 TAP2 has been shown to decrease cartilage degeneration and reduce pain [26]. It is interesting that lubricin (proteoglycan 4, Prg4), produced by the surface cells of cartilage, may concurrently bond with TLR2 and TLR4, thus being capable of inhibiting the inflammatory process in OA [27],[28].
Another important DAMP receptor, RAGE, bonds with glycation end-products (AGEs), besides its reaction to such DAMPs as HMGB1, S100 proteins, and amyloid-β protein. RAGE activation causes noticeable exocytosis and histamine secretion by MCs and increases ROS production, while the cytokine profile remains unchanged [29]. Blocking RAGE with anti-RAGE monoclonal antibody (mAb) causes a dose-dependent reduction in exocytosis [29].
NLRs are “non-classic” DAMP receptors because, rather, they are sensors of pathogen-associated molecular patterns. Nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3 (NLRP3), alongside other proteins, form a multimeric structure named “the inflammasome,” and its activation depends on the TLR activation on a cell [30]. Apparently, NLRP3 plays an important role in the development of OA and synovial inflammation (for detail, see [31]). NLRP3, similar to other DAMP sensors, is expressed in many cells of the synovial membrane, although it is not particularly shown for MCs. However, there is information about the presence of NLRP3 in endometrium MCs, and its activation increases the inflammatory response [32].
2.3. Complement
The complement system is known primarily for its antimicrobial activity, but more and more information is accumulating about the regulatory influence of individual components in non-inflectional inflammation. Components C3, C5, C7, and C9 are found in the synovial fluid of patients with OA [33]. The formation of the last C5b–C9 membrane–attack complex (MAC) enhances the inflammatory response, and the genetic depletion of the C5 and C6 components reduces the severity of cartilage destruction in experimental OA [33]. The complement anaphylatoxins C3a and C5a can be MCs activators and chemoattractants [34],[35]. It is interesting that the mechanism of MCs degranulation differs from that of IgE during complement activation and is associated with the fusion of individual granules with the membrane and the weaker production of cytokines [34]—although, at the same time, the complement potentiates IgE-dependent mast cell activation and degranulation [36].
It has also been shown that MCs themselves can synthesize and secrete complement components C1q, C3, and C5, while secreted tryptase and chymase can cleave C3, converting it into the active form C3a [37]. In general, preliminary in vitro experiments have shown success in preserving chondrocytes by inhibition of C3a with antibodies [38], as well as in reducing cartilage degeneration and inflammation in experimental OA using chondroitin sulfate (CS) E oligosaccharides due to inhibition of the MAC by targeting C5 [39].
2.4. Nerve growth factor (NGF)
As already noted, the number of MCs positively correlates with pain in OA. An important role is played by the activation of MCs by NGF. During inflammation in the joint, NGF production is increased by various cells of the synovial membrane, and the expression of its tropomyosin receptor kinase A (TrkA) receptor on MCs and sensory neurons also increases; in OA, there is a noticeable clustering of peptidergic fibers and MCs. In response to TrkA activation, MCs synthesize prostaglandin D2 (PGD2), which, by activating the DP1 receptors on neurons, leads to the emergence of an action potential and pain sensations [40]. In addition, activation of TrkA on MCs themselves leads to their secretion of histamine, which causes pain hypersensitivity [1],[41].
A systematic analysis of anti-NGF therapy (tanezumab) showed a decrease in pain in patients; however, in some cases, cartilage deterioration was observed, and animal studies have provided conflicting results depending on the timing and dose of the drug [42]. The use of the TrkA blocker AR786 has also been shown to lead to a reduction in pain and, in general, contributed to the reduction of synovitis, although it had no effect on the cartilage itself [43]. Apparently, NGF is not one of the main factors in the development of cartilage damage in OA, although it significantly affects pain.
2.5. Substance P
An important polypeptide neurotransmitter responsible for the appearance of pain is substance P, secreted mainly by afferent fibers, as well as by MCs themselves [44]. A clear colocalization of nerve endings containing substance P with MCs has been shown in OA [45]. Interestingly, the activation of TK by substance P does not occur through interaction with canonical neurokinin-1 receptor (NK1R), but rather through Mas-related G-protein-coupled receptor 2 (MRGPRX2), which leads to the secretion of PGD2, cytokines, and chemokines, attracting more inflammatory cells to focus [1],[46]. In general, this is indirectly confirmed by conflicting data on the use of NK1R blockers for the treatment of OA and the relief of pain [47]. At the same time, MRGPRX2 antagonists clearly prevent the activation of MCs, although their action for the treatment of OA has not yet been shown [48].
3.
Pre-stored mediators
3.1. Biogenic amines
The main mediator pre-stored in MCs granules is histamine. Histamine has many biological functions that depend on its receptor, the primary ones being provided through H1R: Vasodilation, increased vascular permeability, platelet aggregation, and the stimulation of the production of adhesion molecules, cytokines, and chemokines [49]. In the joint, histamine receptors are located on chondrocytes, synovial fibroblasts, various immune cells, and the endothelium [49]. Cross-sectional analysis has shown that H1R blocker intake is associated with a decrease in the severity of OA in patients [50]. Another retrospective study also showed a decreasing trend in structural progression in knee OA while taking antihistamines [51]. However, convincing prospective studies on the effectiveness of antihistamine therapy in OA, including animal models, have not been conducted.
Another important biogenic amine of MCs is serotonin, and it plays an important role in pain formation. Interestingly, serotonin has both hyperalgesic and analgesic effects, depending on the cell type and location. At the periphery, serotonin predominantly potentiates pain, and many of its receptors may be involved in this process [52]. In an adjuvant-induced arthritis model, serotonin depletion reduced the severity of the disease, which may rather indicate a negative role for serotonin [53]. There is also evidence that serotonin is associated with increased pain in rheumatoid arthritis (RA) [54],[55]. In part, this effect may be due to an increase in prostaglandin E2 (PGE2) synthesis by synovial cells [56]. However, the role of serotonin and the regulation of its activity in OA has not yet been studied.
3.2. Proteoglycans
Mast cell proteoglycans are stored in granules and are ionically bound to proteases such as tryptase, chymase, and various exopeptidases. Interestingly, during secretion, the protease–proteoglycan complex remains intact, although tryptase more often dissociates at a neutral pH (for more detail, see [57]). Heparin itself has a known anticoagulant property, although the level of activation of the coagulation pathway increases in arthritis [58]. As a thrombin blocker, heparin may also have a therapeutic effect on OA, although endogenous amounts from MCs are insufficient to detect significant effects [59]. Chondroitin sulfate and hyaluronic acid are important components of the cartilage extracellular matrix and can be used to treat OA [60],[61]. At the same time, it has been shown that chondroitin sulfate and hyaluronic acid are able to stabilize MCs, prevent pro-inflammatory mediator secretion, and reduce their proliferation [62],[63].
3.3. Enzymes
According to the content of neutral proteases, MCs are divided into several subtypes. Tryptase-chymase MCs (MCTC) contain tryptase, chymase, and cathepsin G, and there are also tryptase-only MCT and chymase-only MCC. MCC are localized mainly in the mucous membranes of the gastrointestinal tract, skin, and bronchi [64]. Normally, 60% of all MCs present in the joint are MCTC, but in OA, an increase in MCT is observed, although MCTC remains the same in absolute numbers [65]. In OA, tryptase is primarily known for destroying the extracellular matrix, chondrocyte apoptosis and stimulation of pro-inflammatory molecules secretion by synovial cells [8],[66].
Tryptase has two isoforms, α and β, and β-trypatase has protease activity, while the α form is proteolytically inactive [67]. Interestingly, in OA, the level of β-trypatase in the synovial fluid increases to a greater extent than in RA, and this positively correlates with the level of histamine, which may indicate anaphylactic degranulation of MCs [68]. However, tryptase activity in the synovial fluid has been noted to still be higher in RA than in OA, although tryptase is equally elevated in the synovial membrane [69]. Apparently, in OA, the greater amount of tryptase is compensated by a decrease in its activity.
Interestingly, the expression of protease-activated receptor (PAR)-2 on the MCs in OA is very low, that is, tryptase does not additionally activate MCs, stimulating them in the synthesis of pro-inflammatory mediators, such as IL-8 [69]. However, in OA, PAR-2 expression is increased in chondrocytes, apparently after activation by pro-inflammatory cytokines IL-1β, TNFα, and transforming growth factor β (TGFβ) [70]. In turn, this increases cartilage degradation, premature aging, and chondrocyte death [71]. The use of the PAR-2 antagonist AZ3451 or monoclonal antibodies prevents this effect and reduces the severity of OA in animals [71],[72]. In addition, PAR-2 is present on osteoblasts and osteoclasts of subchondral bone, and its activation leads to an imbalance in osteogenesis and bone resorption [73]. Inhibition of tryptase itself by APC366 has been shown to significantly reduce cartilage damage, osteophyte formation, and synovitis in experimental OA [8].
The enzymes secreted by MCs also include arylsulfatases, carboxypeptidase A, kinogenases, MMPs, peroxidases, and phospholipases, which actively degrade the extracellular matrix. In general, MCs are not a unique source of these enzymes, as they are also produced by synovial membrane cells, chondrocytes themselves, blood cells, etc. At the same time, therapy aimed at suppressing the activity of proteases has therapeutic potential in OA (discussed in more detail in [74],[75]).
3.4. Polypeptides
As part of MCs granules, various polypeptides involved in the regulation of the inflammatory response are stored. In general, these polypeptides are not a unique product of MCs and are synthesized by many other types; however, the pathophysiological effect of these mediators cannot be ignored. It has been shown that the concentration of CRH [76], endothelin-1 [77], and bradykinin [78] increases in the synovial fluid of patients with OA. Endothelin-1 has a catabolic effect on cartilage, increasing the secretion of MMP-1 and -13, and NO by articular chondrocytes and synoviocytes [79]–[81], and blockade of the ETB receptor alleviates the OA-like cartilage phenotype [82]. Bradykinin is a pro-inflammatory mediator and induces the secretion of PGE2, IL-6, and IL-8 by synoviocytes and chondrocytes, and blockade of its B2 receptor by Icatibant and Fasitibant has a therapeutic effect in OA [78],[83].
Some of the MCs peptide mediators may be protective in OA. Somatostatin and its chimeric peptide with a growth hormone fragment have therapeutic potential in OA, with the latter even reducing cartilage degradation to a greater extent than hyaluronic acid [84],[85]. Urocortin is able to inhibit the induced apoptosis of chondrocytes, and the mechanism seems to be related to the influence on Ca2+ influx and regulation of the mechanosensitive channel by the Piezo1 channel [86],[87]. Vasoactive intestinal peptide, which is also produced by nerve endings, plays a role in the pathogenesis of pain in OA. On the one hand, there are data showing the pro-inflammatory effect of VIP, which consists of sensitizing nerve endings, as well as stimulating the production of pro-inflammatory cytokines, but on the other hand, its modulating effect on the CRH system, particularly on increasing the expression of urocortin, shows its anti-inflammatory side [88]. Interestingly, the MCs tryptase and chymase can cause degradation of VIP and substance P, which makes the system of interaction between various MCs mediators even more complex [89].
4.
De novo synthesized mediators
When activated, MCs, like many other immune cells, also begin to synthesize and secrete various inflammatory mediators, such as cytokines, chemokines, growth factors, arachidonic acid metabolites, and nitric oxide. The role of most of these in the development of OA deserves a separate detailed consideration; herein, we briefly consider their main functions.
4.1. Cytokines
The most powerful inducers of cartilage degradation are the members of the IL-1 family IL-1α and IL-1β. In OA, IL-1 stimulates the synthesis of MMPs and inhibits the synthesis of type 2 collagen and proteoglycans by chondrocytes, providing a catabolic effect, and stimulates the secretion of IL-6 and TNFα, providing a pro-inflammatory effect. The use of recombinant interleukin 1 receptor antagonist (IL-1RA), a protein of the IL-1 family that has an inhibitory effect on IL-1α and IL-1β signaling, has shown a pronounced protective effect in animal models, although it has failed in clinical trials [90],[91].
The second most important cytokine involved in the pathogenesis of OA is TNFα. Its catabolic and pro-inflammatory effects are well known [92],[93]. The use of various approaches for TNFα inhibition may improve the state of patients with OA, as well as improve the results of other therapies [94].
In cartilage, MCs are one of the main sources of IL-17, although the production of the cytokine itself increases to a greater extent in RA [95]. Nevertheless, the pro-inflammatory effects of IL-17 have been described [96], partly due to its tandem action with IL-1 [97].
IL-6 is usually referred to as a pro-inflammatory cytokine; however, its role in OA is not actually so clear. On the one hand, an increase in its amount in synovial fluid in OA and its concomitant catabolic effects are clearly shown [98], but on the other hand, it is able to inhibit other pro-inflammatory agents, which partly determines its protective effect (for detail, see [99]). Nevertheless, the blockade of IL-6 itself or its receptor with antibodies may be a promising strategy for the treatment of OA [99].
Interferon γ (IFNγ) can suppress the synthesis of MMPs by chondrocytes [100], as well as reduce the IL-1β-stimulated production of IL-8 and IL-10 [101]. However, synergistically with IL-1, IFNγ enhances the production of IL-6, NO, and PGE2, which can be attributed to the pro-inflammatory effect of the cytokine, which makes its role in the pathogenesis of OA also ambiguous [101].
IL-3 is an anti-inflammatory MCs mediator, although it is also secreted extensively by T cells and monocytes/macrophages. In OA, IL-3 is able to reduce the secretion of MMPs by chondrocytes and, in an in vivo model of OA, reduce cartilage and subchondral bone degeneration [102]. The anti-inflammatory cytokines IL-4 and IL-10, secreted by a wide variety of immune cells, also have chondroprotective and analgesic effects [103]. IL-13, which is also produced in large amounts by T-helpers, reduces the secretion of IL-1β and TNFα in the synovial membrane [104] and can also presumably reduce the expression level of adamalysin metalloproteinase 15 (ADAM15) [105].
4.2. Growth factors
In addition to a wide range of cytokines, MCs secrete various growth factors that are responsible for the regulation of the inflammatory process and tissue remodeling. The action of growth factors such as SCF, which is responsible for mast cell recruitment, and NGF, which mediates pain, have been described above.
Granulocyte–macrophage colony-stimulating factor (GM-CSF) appears to play a significant role in the pathogenesis of OA, particularly in pain. GM-CSF blockade with monoclonal antibodies reduces pain and cartilage degradation in experimental OA, although therapy should be continual in the later developmental stages [106],[107]. The mechanism of pain development during GM-CSF stimulation is not associated with a direct effect on neurons, but with an effect on macrophages, which release factors that activate nociception [108].
The concentration of basic FGF (FGF2) increases in the plasma and synovial fluid of patients with OA and positively correlates with the degree of cartilage damage, as well as with the number of MCs in the synovial tissue [109]–[111]. FGF2 is able to activate the synthesis of MMP-13 by chondrocytes, which leads to the degradation of the cartilage extracellular matrix [112]. On the contrary, exogenous FGF2 is used to repair joint tissues, especially in the focal defect model, where it is able to increase the expression of collagen-2 and aggrecan, although it strongly promotes fibrosis, which makes it unpromising for the treatment of articular cartilage diseases [113]–[115]. It is assumed that the difference in the effects of FGF depends on the balance between the expression of its two receptors: FGFR1 seems to mediate catabolic activity, and FGFR3 is responsible for anabolic prochondrogenic effects [116].
Another important growth factor secreted by MCs is vascular endothelial growth factor (VEGF). In general, its most important effects include stimulation of the secretion of IL-1, IL-6, and MMPs, which have a catabolic effect, as well as stimulation of vascular growth, which promotes osteogenesis and osteophyte formation [117]. Inhibition of VEGF by monoclonal antibodies is considered a potential therapy for OA [118].
4.3. Phospholipid metabolites
One of the most important signaling molecules activated during inflammation is phospholipase A2 (PLA2) and activation of the downstream metabolism of arachidonic acid. As a result of cyclooxygenase-2 (COX-2) activity, prostaglandins and thromboxanes are formed, and as a result of lipoxygenase activity, leukotrienes (LT) are formed [119]. This pathway is characteristic of many cell types, including MCs that predominantly secrete LTB4, LTC4, and PGD2 [120].
LTB4 and its metabolite LTC4 have not been shown to be clearly involved in the pathogenesis of OA in vivo, although some of its pro-inflammatory properties, consisting of increased neutrophilic inflammation, have been described for RA [121],[122]. Targeted therapy directed against LTB4 has not shown much effectiveness in RA [121], and in OA, no significant effect of LTB4 on chondrocytes has been observed [123]. Experiments with synovial membrane explants have shown that LTB4 is able to stimulate the synthesis of IL-1β and TNFα [124].
PGD2 is synthesized by MCs in greater amounts in RA than in OA; however, in both cases, it has a pro-inflammatory effect, partly mediated by neutrophil recruitment [125], as well as costimulation of the production of COX-2 by chondrocytes [126]. The role of PGD2 in the pathogenesis of pain induced by NGF and substance P has been described above. On the contrary, when acting on chondrocytes themselves, PGD2 can reduce IL-1-induced MMP-1 and MMP-13 expression [127] and NO synthesis [128]. Moreover, deletion of the DP1 receptor leads to a worsening of OA [129]. This difference in effects seems to be determined by the concentration of PGD2 [128].
In general, COX-2 blockers (non-steroidal anti-inflammatory drugs) reduce pain and have a chondroprotective effect [130], while steroid drugs that block PLA2 activity seem to be effective only for a short period of time [131].
4.4. Nitric oxide (NO)
During inflammation in the joint, NO synthesis is triggered by both the chondrocytes themselves and the cells of the synovial membrane, including MCs. Inhibition of inducible NO synthase (iNOS) leads to a decrease in the synthesis of MMPs, IL-1β, and COX-2 [132]. Moreover, the effects of NO include a decrease in the synthesis of collagen-2 and proteoglycans and an increase in the synthesis of MMP-9 by chondrocytes, and can also stimulate apoptosis, largely due to the combination with superoxide anions and the formation of peroxynitrite (for more detail, see [133]). Recent data confirm that NO blockade is able to reduce COX-2 and MMP-3 expression and increase collagen-2 and aggrecan expression in chondrocytes, as well as prevent cartilage degradation in experimental OA [134].
5.
Conclusions
MCs play a significant role in the pathogenesis of OA. It is worth noting that in addition to regulating the progression of the disease itself, MCs appear to be largely responsible for the initiation of inflammation in trauma and the onset of pain. MCs-targeted therapy, especially affecting the individual links in mast cell activity, may be promising for the treatment of OA (Figure 1). Moreover, new therapies can be directed at different parts of the MCs response, and can be different in time, simulating the dynamics of the inflammatory response development. Various nanoparticles, microspheres, hydrogels, liposomes, etc. can be suitable for this [135],[136]. Thus, it is possible to develop drug systems that differentially regulate only the activity of MSs and thereby affect other links of the inflammatory response.
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