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Endod Dent Traumatol 2000; 16: 1–8 Copyright C Munksgaard 2000 Printed in Denmark . All rights reserved ISSN 0109-2502 Macrophages in periapical lesions Metzger Z. Macrophages in periapical lesions. Endod Dent Z. Metzger
Traumatol 2000; 16: 1–8. C Munksgaard, 2000.
Department of Oral Biology, Goldschleger Schoolof Dental Medicine, Tel Aviv University, Tel Aviv,Israel and Department of Endodontics, University Abstract – Macrophages are major constituents of periapical granu- of North Carolina at Chapel Hill, Chapel Hill, North lomas. They have a central protective role in both innate immunity and adoptive, antigen-specific immune response. Macrophage acti-vation may occur in periapical granulomas by cytokines producedby antigen-activated T-lymphocytes; by bacterial endotoxin, as partof the innate immunity; or by both these processes. Recent studiesin athymic animals have shown that periapical granulomas maydevelop independently of T-lymphocytes. This observation revealsthe major role that the activated macrophage may have in the Key words: apical periodontitis; macrophages; formation of periapical lesions. Only a few of the macrophages in periapical granuloma the periapical granuloma are activated. Current studies indicate Zvi Metzger, The Goldschleger School of Dental that these activated cells are the source of the bone-resorbing Medicine, Tel Aviv University, Ramat Aviv, cytokines in the periapical granuloma. Understanding the central Tel Aviv 96978, Israel role of the activated macrophage in the formation as well as the Fax: π972 3 6409250e-mail: metzger/post.tau.ac.il perpetuation of periapical lesions may lead to the development ofnew diagnostic and therapeutic tools in endodontics.
Accepted August 30, 1999 Periapical lesions are an expression of the host re- specifically identify plasma cells in periapical lesions sponse which actively prevents dissemination of bac- by their immunoglobulin content were reported. In teria from the infected root canal into the surround- the last decade, intensive use of monoclonal anti- ing bone. The cells involved in this process include bodies against subsets of T-lymphocytes, B-lympho- B- and T-lymphocytes, plasma cells and the ‘‘pro- cytes, macrophages, dendritic cells, as well as plasma fessional'' phagocytes: macrophages and PMNs. The cells and PMNs, resulted in a major breakthrough in engagement, phagocytosis and killing of bacteria are the understanding of the immunobiology of periapical the main tasks of the periapical host response; never- host response, in both naturally occurring human theless, formation of these lesions is associated with periapical lesions and those experimentally induced bone loss in the area surrounding the root apex. The resulting radiolucent periapical lesion is one of the Cells with a distinct morphology such as PMNs, main clinical manifestations of this inflammatory re- mast cells and osteoclasts have always been identifi- sponse, and its progress or healing is commonly able. This was also the case with lymphocytes as a evaluated by the size and morphology of the lesion as group, but not with macrophages. In earlier studies shown on a radiographic image.
only cells with a classic macrophage morphology Qualitative and quantitative studies of the cellular could be identified as such. Currently available mono- composition of periapical granulomas have been pro- clonal antibodies make it possible to identify macro- foundly influenced by the methodology available at phages of diverse morphology and recognize subsets the time. Initial attempts to characterize the cells par- of these cells.
ticipating in these lesions were based on the classic The purpose of the present review is to examine morphology of the cells. Electron microscopy and the role of macrophages in the formation and main- histochemistry followed later. With the introduction tenance of these lesions, as it gradually emerges from of immunohistological methods, the first attempts to the vast literature on this subject.
inate the invading microorganisms. Macrophages Presence of macrophages in periapical lesions
present in the periapical granuloma contribute by The presence of macrophages in human periapical their function as phagocytes to effectively preventing inflammatory lesions has been a common and fre- the dissemination of bacteria from the infected root quently reported finding. Macrophages constitute up to 46% of the periapical inflammatory cells found in Macrophages may also serve as ‘‘antigen-present- tissue sections of human periapical granulomas (1).
ing cells'' in the essential initial steps of the induction When Stern et al. (2) dispersed periapical granulomas of acquired immunity. They process the antigen and to cell suspensions, 30% of the resulting cells were present it to the antigen-specific clones of T-helper macrophages. Macrophages were also found to be the lymphocytes by a process involving the recognition predominant inflammatory cell when Kopp & by the lymphocytes of an MHC II molecule on the Schwarting (3) used monoclonal antibodies to identify macrophages. Additionally, they produce the cytokine them in human periapical lesions. Piattelli et al. (4) IL-1, which is an essential complementary signal for have similarly reported that macrophages outnumber the activation of these lymphocytes. Macrophages T-lymphocytes in human periapical granulomas.
that carry MHC II molecules, and thus may serve as In the rat model, Kawashima et al. (5) recently antigen-presenting cells, have been identified in peri- demonstrated that macrophages are the predominant apical granulomas in both humans and the rat model immunocompetent cells throughout the development (termed also HLA-DR or Ia antigen-positive cells) (3, of the lesion. The kinetics of their presence in these experimental periapical lesions were studied by Aka- Macrophages are considered a main source of the mine et al. (6) who followed the periapical lesions for cytokines IL-1a IL-1b and TNFa, which contribute as long as 150 days. Macrophages increased in num- to the initiation and regulation of the inflammatory bers during the first 10 days, maintained this level process. Additionally, they produce a plethora of through day 60, and declined gradually thereafter.
other active molecules, including metallo-proteases(collagenase, elastase), and prostaglandins, which mayalso contribute to the destructive outcome of the peri- Potential role of macrophages in the periapical
apical inflammatory process. Some of these products directly damage connective tissue constituents, while Macrophages have central roles in (a) innate, nonspe- others, including the cytokines produced by the cific immunity; (b) the onset, regulation and outcome macrophages, activate other cells to either (a) destruc- of antigen-specific, acquired, immunity; and (c) the tive action such as osteoclast activation and bone re- regulation of connective tissue destruction and repair.
sorption or (b) the constructive process of repair by Macrophages are professional phagocytic cells that activating fibroblast proliferation and collagen pro- can internalize and kill bacteria by several mechan- duction by these cells.
isms, some of which are part of the innate immunity Though it is commonly assumed that all of the while others require the presence of specific anti- above long list of potential activities of the macro- bodies against the bacterium and should be con- phage take place in the periapical granuloma, it is not sidered part of the effector arm of specific, acquired essentially true. Certain processes may be active while immunity. Bacteria that are new to the host may acti- others may rarely occur in this lesion. Similarly, it is vate the complement system by the alternative path- commonly implied that all macrophages perform all way, resulting in their opsonization by the C3b com- the above tasks, which similarly is erroneous: subsets ponent. This in turn will result in their phagocytosis of these cells, which may exist in relatively small num- by the macrophages via a C3b-receptor-mediated bers, may be responsible for a specific activity. Emerg- process. Other bacteria may attach to the macro- ing evidence indicates that some of these functions, phages through lectin-mediated mechanisms, leading such as active production of IL-1, involve only a few to lectinophagocytosis, which is independent of the activated macrophages, which in chronic human peri- common receptor-ligand binding (7). Once specific apical granulomas do not exceed 2%–3% of the antibodies to a bacterium are present, either develop- macrophages present in these lesions (9).
ing through the course of the current infection or asresult of a former encounter with this bacterium, a Evolvement of the immunobiological concept of
most efficient form of phagocytosis will occur, involv- ing dual opsonization by IgG and C3b and the en-gagement of both the Fc and C3b macrophage recep- Studies that aim to elucidate the immunobiology of periapical lesions may roughly be divided into three It is the innate immunity that enables the host to eras. Early studies concentrated on the production survive the initial steps of infection, while the ac- and function of immunoglobulins in these lesions.
quired, specific, immunity allows it to efficiently elim- Next, the specific T-lymphocyte function was empha- Macrophages in periapical lesions
sized and their subsets meticulously studied in relation ripheral blood. These findings were interpreted as an to periapical inflammation. The third and current era initial active function of T-lymphocytes, which is later has been initiated by the use of immunodeficient ani- down-regulated and controlled by T-suppressor cells.
mal models such as athymic and ‘‘knock-out'' ani- The balance of their action is expressed in chronic mals, which reveal the central role that macrophages periapical lesions, such as those encountered in have in this complex local host response.
In the long-term perspective the inevitable con- clusion is that the availability of new methodologies Protective function of T-lymphocytes in periapical
influenced the type of studies performed and eventu- ally affected the evolvement of the immunobiologicalunderstanding of the complex nature of periapical A protective role of T-helper lymphocyte function host response.
should eventually be expressed as a better ability of Initially, the commercial availability of specific anti- the host to prevent bacteria from spreading from the bodies directed against human IgG, IgM, IgA and infected root canal. This may be accomplished by (a) IgE allowed immunofluorescent or immunohisto- producing antibodies locally and (b) increasing the lo- chemical detection of these molecules in periapical cal availability of phagocytes and enhancing their lesions, either in a free form or as a marker of subsets function (Fig. 1). Local activation of antigen-specific of B-lymphocytes and plasma cells. Later, the combi- T- helper lymphocytes is a prerequisite for a local nation of these antibodies with those directed against production of antibodies specific to the bacteria that human complement allowed the demonstration of ac- periodically emerge from the root canal (16, 17). This tivity rather than the simple presence of immunoglob- in turn will enable the effective opsonization of the ulins in periapical lesions: Johannessen et al. (10) have bacteria, followed by phagocytosis and killing.
demonstrated intracellular colocalization of IgG and Local macrophage activation is accomplished C3b in macrophages in periapical inflammatory mainly by g-interferon produced by the activated T- lesions, suggesting phagocytosis of bacteria by dual helper cells (Fig. 1). Even though the activation of the opsonization by both opsonins.
lymphocytes is antigen-specific, once macrophages At a later stage, the availability of monoclonal anti- are activated, the effector result will be nonspecific, bodies against T-lymphocyte subsets made it possible and their phagocytic and killing abilities will be to explore the presence of these cells in both human greatly enhanced. IL-1 production by activated periapical lesions as well as in those experimentally macrophages will locally elevate CAM-1 molecule ex- induced in rats. T-cells in human periapical granu-lomas were studied by Cymerman et al. and others(11–13). It became apparent that both T-helper andT-suppressor lymphocytes are present in these lesions(11). In delayed hypersensitivity in humans, a typicalT-helper to T-suppressor relation is about 2:1 (14). Itwas therefore of interest to define whether T-lympho-cytes in periapical lesions follow this trend. Babal etal. (12) have found a T-helper to T-suppressor ratiowhich was ∞1.0 in periapical granulomas, while Bar-khordar & Desouza (13) report a ratio of ∂1.0.
Therefore, it seems that the predominance of T-helper lymphocytes, which is typical of delayed hyper-sensitivity, does not exist in the chronic periapicalgranuloma. Nevertheless, this is not a uniform find-ing, as Kopp & Schwarting (3) found a T-helper toT-suppressor ratio of 3:2 in periapical granulomas,which diminished to ∂1.0 in periapical scars.
The rat model allows a further insight into the kin- etics of T-lymphocyte subsets in the developing peri-apical lesion. Stashenko & Yu (15) demonstrated that Fig. 1. Protective role of activated macrophages and T-lymphocytesin periapical granulomas. T-lymphocyte activation leads to antigen- during the early, active, phase of lesion development specific B-lymphocyte activation and local production of specific T-helper cells predominate while at the later chronic antibodies. It also leads to macrophage activation, which will result stage T-suppressor cells outnumber the T-helper cell in enhanced phagocytosis by these cells, as well as in cytokine- population. The initial T-helper to T-supressor ratio mediated enhanced PMN margination, chemotaxis and their acti- of 1.7 turned at the later stage into ∞1.0, as com- vation. Macrophage activation may also be achieved independently pared to a T-helper to T-supressor ratio of 2.0 in pe- of T-lymphocytes by bacterial endotoxin (LPS).
pression by endothelial cells in the capillaries, thus glandins (21), bacterial endotoxin (22), complement enhancing the local attachment of PMNs and mono- activation products, as well as the inflammatory cyto- cytes and enhancing their migration into the area.
kines IL-1a, IL-1b, TNFa, TNFb, IL-6 and IL-11 IL-8 produced by these macrophages will chemo- which, as a group, were previously referred to as ‘‘os- tactically attract the PMNs and activate them, making teoclast activating factor'' (OAF) (23). Among these them more available and more competent to engage IL-1b is the most active cytokine and its bone-re- and kill the bacteria (Fig. 1). Activation of the macro- sorbing capacity is 13 times that of IL-1a and 1000 phages has a major role in maintaining the two lines times that of TNFa or TNFb (24).
of phagocitic cell defence, typically described in the All of these have been mentioned in relation to the periapical lesion: an inner area, closer to the apex, in periapical bone resorption associated with infected which PMNs predominate; and around it the area in root canals. The question is which of these potential which the phagocytic macrophages are seen (5).
bone-resorbing stimuli is actually involved in activating Therefore, the defensive function of T-helper the osteoclasts in these lesions? lymphocytes is achieved indirectly through allowing Two recent studies by Wang & Stashenko (25, 26) the activation of (a) specific B-lymphocytes to become provided convincing evidence that among the long plasma cells and produce antibodies and (b) nonspec- list of potential mediators that may activate osteoclasts ific effector cells: the macrophages. In order to avoid and cause periapical bone resorption, the main and an endless loop of mutual activation of macrophages most important in human chronic periapical lesions and T-lymphocytes, the process is actively controlled are IL-1b and TNFb. In the rat model of active peri- and down-regulated by T-suppressor lymphocytes.
apical bone resorption, IL-1a and, to a lesser extent The essential role of the T-lymphocytes in the pro- IL-1b and TNFb, are the major bone-resorbing cyto- cess is generally acknowledged. The first studies that kines. Both studies indicate that osteoclast activation used athymic mice and rats to study the formation by these cytokines is mediated by the formation of of periapical inflammatory lesions were accordingly cyclooxygenase pathway products such as prosta- designed to finally ‘‘nail down'' the critical role of T- glandins, as the effect could be significantly blocked lymphocytes in the formation of these lesions (18, 28).
by nonsteroid anti-inflammatory drugs (NSAID) (25, As it transpired, these studies are the turning point in proving otherwise. Both demonstrated that periapical The formation of periapical lesions was studied in lesions can develop independently of T-lymphocyte ac- the rat model by Kakehashi, Stashenko and others (5, tivity, thus leaving the stage to the other key actor: 15, 27–30). Following the exposure and contami- the macrophage (as will be detailed below).
nation of the pulp and root canal, an inflammatoryresponse is activated in the periapical region. This isassociated with a rapid growth of a periapical lesion Bone resorption in periapical lesions
whose size can be monitored using either radiographs Bone resorption in the periapical region is one of the or histologic sections. This rapid growth persists for clinical hallmarks of periapical pathosis. Host defense 15 days and is associated with ‘‘bone-resorbing activ- against the spread of bacteria from the infected root ity'' that can be detected in homogenates of the canal does not depend directly on bone resorption in lesions and measured using an in vitro bone resorption the area. The resorption may be viewed as either an assay (29). Following the active resorptive phase, the undesirable byproduct of the host response, as is the size of the lesions remains stable for up to 30 days case with periodontal disease, or alternatively as a (29). During this stationary phase the bone-resorbing process by which the bone is removed from a risky activity declines to 10%–30% of that in the active area, thus allowing a ‘‘buffer zone'' to be formed, in growing stage. This stationary phase is considered an which host-response constituents engage the bacteria equivalent of an existing, chronic, periapical granu- (20). In either case, it is bone resorption in the peri- loma in humans which also contains bone-resorptive apical area which serves the clinician as a major indi- activity (25).
cator for either progress of disease or repair of the The cytokines defined in the above studies are periapical lesion. As such it has been thoroughly found in human periapical lesions in measurable studied in both humans and animal models.
amounts. Lim et al. (31) found significant amounts ofIL-1b in homogenates of human periapical lesions,even though none of the patients had detectable Potential vs actual bone-resorbing agents
serum levels of this cytokine. Noninflamed pulp tissue Bone resorption occurs through the activation of the that served as control was also free of the cytokine.
bone-resorbing cells: the osteoclasts. A wide range of Periapical exudates were studied by Matsuo et al. (32) biologically active molecules have been demonstrated for their IL1-a and IL-1b content. Exudates, ob- to have the capacity to activate osteoclastic bone re- tained through the root canal, contained an average sorption in in vitro models. These include prosta- level of 6.57(∫0.73) ng/ml of IL-1-b and 3.23 Macrophages in periapical lesions
(∫0.66) ng/ml of IL-1a. The cytokine profile tissue responses of conventional and athymic rats (18).
changed following root canal treatment with a ten- A similar result is reported by Tani-Ishii et al. (28) dency of IL-1a to increase and of IL-1b to decrease.
who used athymic mice. They also found that peri-apical lesions develop in animals lacking T-cells at arate that precludes the possibility that T-lymphocytes Cellular sources of bone-resorbing cytokines
are an essential prerequisite for the development of Although IL-1 and TNF may be produced by many these lesions. Even though T-lymphocytes may, and cell kinds, the activated macrophage is considered the most probably do, usually contribute to the process, main source of IL-1a, IL-1b and TNFa (33). On the alternative routes exist that enable the formation of other hand, TNFb is commonly considered an acti- the lesions in their absence.
vated T-lymphocyte product (34).
The activated macrophage may serve as such a route In view of the above, two cell types should be con- in the formation of periapical lesions. Macrophage ac- sidered responsible for bone-resorbing activity in peri- tivation may occur by a variety of pathways. Cytokines apical lesions: activated T-cells and activated macro- such as g-interferon, which are produced by antigen- phages. Not all T-lymphocytes or macrophages in the specific activated T-lymphocytes, are the main im- periapical lesion are in a state of activation. Kopp & mune-response-related activators of the macrophage Schwarting (3) found that only 20% of the T-lympho- (33, 38). Nevertheless, in their absence, bacterial endo- cytes in human periapical granulomas are activated.
toxin (LPS) may successfully accomplish this task (35, Artese et al. (9), who also used human periapical 39, 40). This activation of the macrophage may be granulomas, demonstrated that while 41% of the viewed as part of the innate immunity, which is inde- mononuclear inflammatory cells are macrophages, pendent of specific response to antigens. This may be a only 2%–3% of these cells are activated and produce mechanism by which the lesions developed in the IL-1b and TNFa, which were used in this study as athymic animals. The bacterial content of the infected markers of their activation (9). Therefore, it seems root canals in these animals gradually developed to a that a rather small part of the cells in the periapical 46% gram-negative flora (41). LPS derived from these granuloma are of potential importance as the source gram-negative bacteria could activate macrophages in of bone-resorbing activity in these lesions. It may not the periapical area. These cells, in turn, produce their be the total number of T-lymphocytes or macro- cytokines IL-1a, IL-1b and TNFa, which activate os- phages in the lesion that is important but rather the teoclastic bone resorption. This does not preclude par- number of activated cells of each kind.
ticipation of the T-cell in the process in normal ani- The states of activation of these cells are closely mals, but rather turns the spotlight on the main effector related to each other: T-helper lymphocytes may be cell: the macrophage. This is also in agreement with the activated in an antigen-specific manner by antigen- finding that in the rat model IL-1a is the major bone- presenting macrophages which also produce the IL-1 resorbing cytokine while TNFb, the T-cell product, required for this process. Macrophage activation, as could not be detected in these lesions, neither in anti- part of the acquired, specific, immune response, may body-blocking nor in immunohistochemical studies be achieved by cytokines such as interferon-g, pro- duced by the activated T-lymphocytes (Fig. 1). Never-theless, macrophages may also be activated by otherroutes, such as exposure to bacterial endotoxin (LPS), Kinetics of macrophage infiltration in periapical lesions
as part of the innate, nonspecific immunity (35).
The unique study by Akamine et al. (6) followed ratperiapical lesions for as long as 150 days. Analysis Studies in athymic animals
of their data reveals that the active growing stage of Athymic rats and mice are powerful tools to study periapical lesions in the rat, which lasted for the first and demonstrate the essential role of T-lymphocytes, 60 days, coincides with a peak of macrophage pres- in immunobiologic processes (36, 37). These animals ence in the lesion. When active growth stops and a lack T-cells, and consequently T-cell function is miss- stationary stage is reached, the presence of macro- ing in a variety of immune responses which are thus phages in the lesion gradually declines. This may be a inactive. Such animals were recently used in two coincidence; nevertheless, it may express a significant studies, and it was assumed that periapical bone re- correlation. Further support for this notion may be sorption and development of periapical lesions will be found in a recent study by Kawashima et al. (5) who defective. The results of these studies should be view- showed that macrophage infiltration in the periapical ed as a turning point in understanding the immunobi- lesions is associated with bone resorption in the area.
ology of the host response and bone resorption in In their study, macrophage infiltration preceded that periapical lesions. Wallstrom et al. (18) demonstrated of lymphocytes and gradually increased throughout that no significant difference exists between periapical the 56 days of the experiment.
IL-1 and macrophages in the periapical granuloma
The presence of IL-1b in association with a subpopu-lation of the macrophages in periapical lesions hasbeen reported by several investigators (9, 30, 42). Ar-tese et al. (9) reported that in established human peri-apical granulomas, there are very few cells with im-munoreactivity of IL-1b and TNFa and that thesecells have a macrophage morphology. Tani-Ishii et al.
(42) demonstrated in the rat model that IL-1a andTNFa are associated with macrophages in the peri-apical lesion as soon as 2 days after exposure of thepulp. They persisted through the 30 days of the ex-periment. In contrast, TNFb and IL-1b could not bedetected in the sections.
Nevertheless, the presence of cytokines in association with these cells does not essentially prove that theyare the source of these molecules. For example, IgE Fig. 2. Elimination of macrophage-derived destructive mediators.
is found in specific association with basophils and (A) Traditional method: by root canal treatment, eliminating acti-vation stimuli such as bacterial antigens and LPS. (B) Proposed mast cells, even though it is a plasma cell product method: by pharmacological agents such as steroids, tetracyclines, that attaches itself to a receptor on the former cells.
receptor antagonists or NSAIDs, which interfere with mediators' Similarly, the cytokine may potentially have been at- production or action.
tached to, or taken into, these cells, rather than pro-duced by them. Recently, direct proof was providedwhich clearly demonstrates that the activated macro-phages in fact produce IL-1b in periapical lesions. In tissue repair and bone repair from taking place (19, an in situ hybridization study, Hamachi et al. (30) demonstrated the presence of messenger RNA for IL- If this is true, it might be important and possible 1b in the macrophages. This proves not only that to monitor their state of activation by sampling the these cells are capable of producing cytokines in gen- interstitial fluid of the lesion through the root canal eral and that the cytokines are associated with them (32, 43). Recently Kuo et al. (43) were able to measure in the periapical lesion, but also that subpopulations the IL-1b content of apical exudates and correlate it of macrophages are actively engaged in producing this with clinical and radiological features of the lesions.
cytokine in periapical granulomas.
A longitudinal study to establish a correlation be-tween the diminishing IL-1b content of the lesionsand their gradual radiographic repair will be required to prove this point.
Endodontic treatment aims to eliminate bacteria from Assuming that such inhibitory mechanisms are in- the infected root canals, which will later be sealed, to volved in the prolonged and delayed repair of peri- prevent recontamination. With the bacterial stimuli apical lesions, pharmacological modulation of the that evoked the periapical inflammation gone, the process may be considered (Fig. 2). Stashenko et al.
periapical lesion should resolve, and repair should (23) demonstrated that IL-1 receptor-antagonist may take place. Nevertheless, healing of the lesion may be used in animals to reduce bone-resorbing activity take many months. It may be argued that if the lesion and the formation of periapical lesions. Similarly, eventually heals in 12 months, there is no benefit in NSAIDs were successfully used for a similar purpose rushing the process. Nevertheless, this may have clin- in experimental and human periodontal diseases, as ical importance, as it may allow earlier decisions to well as in the cat model for periapical lesion (44, 45).
be made in regard to the restorative treatment plan These two approaches are directed at either blocking for the treated teeth.
the binding of the already produced cytokine to its tar- This prolonged healing process raises the possibility get cells or interfering with its action on osteoclasts and that the activated cells in the lesion may maintain osteoblasts, which involves prostaglandin production their state of activation long after the initial cause of their activation has been eliminated.
Tetracyclines may be used to inhibit cytokine secre- Macrophages are known to persist in the tissues for tion by activated macrophages (46). Shapira et al. (46) many months and if their state of activation persists, studied tetracycline inhibition of TNF and IL-1 pro- they may inhibit the fibroblasts and maintain osteo- duction by LPS-activated macrophages and found its clast activity, thus preventing both soft connective effect to be at a post-transcriptional level: both m- Macrophages in periapical lesions
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