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Keywords:

  • alternatively activated macrophages cestodes;
  • trematodes;
  • nematodes

SUMMARY

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Macrophages play crucial roles in the immune response, as they can initiate, modulate and also be final effector cells during immune responses to infections. Macrophages are derived from myeloid precursor cells in bone marrow and are widely distributed in every tissue of the body. Over the past 10 years, the concepts about macrophage activation have clearly changed; macrophages are not called activated or inactivated as they used to be. These changes in the concept of macrophage response is the result of many in vitro and in vivo studies, but the major support for the current concept of alternatively activated macrophages (AAMφ) comes from parasitic helminth infections. Parasitic helminths have developed complex mechanisms to evade and modulate host immunity. Infections with these parasites induce strong polarized Th2-type immune responses frequently associated with impaired T-cell proliferative responses to parasitic or unrelated antigens. Given the recent advances in understanding the immunoregulatory capabilities of helminthic infections, it has been suggested that macrophages can be a target for immunomodulation. Furthermore, they become altered when a host experiences chronic exposure to helminth parasites or their by-products, which favour the induction of AAMφ. How AAMφ participate in modulating host immunity during helminth infections and what their roles are in clearing or favouring parasite survival remains elusive. Here we review the most recent advances in the literature on AAMφ at the host–parasite interface, including three classes of helminths: nematodes (Brugia, Nippostrongylus, Litomosoides, Heligmosomoides), trematodes (Schistosoma, Fasciola) and cestodes (Taenia, Echinococcus, Hymenolepis).


PARASITE HELMINTH DIVERSITY

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Parasitic helminths are a highly diverse group of organisms which display very different morphologies, accessory structures, sexual and feeding behaviours as well as life cycle stages. Likewise, they also generate a variety of diseases and allocate into a variety of niches in their hosts, ranging from spending their entire life in a specific organ or tissue, such as the gastrointestinal tract, to travelling into different organs and systems in the host (skin, bladder, muscle, liver, lung and brain), to finally establish in a specific organ where they may cause disease. Helminth parasites also appear to follow extremely varied and complicated routes of infection of host tissues. Infections mainly originate following ingestion of eggs/larvae (oral route) or through active penetration of the skin by parasite larvae or the bite of their vectors (cutaneous route).

After oral infection, some parasitic nematodes remain in the gastrointestinal tract for the rest of their life. The infective larvae of some nematode parasites, however, penetrate the intestinal wall and are transported by blood flow to the liver or other organs, transiently passing through the lungs or heart.

The migration profiles of the major trematode parasites differ significantly from those of gastrointestinal nematodes. The blood flukes (schistosomes) also follow the percutaneous route to the lungs, but are then carried to and settle in the mesenteric veins (Schistosoma mansoni). The liver flukes (Fasciola hepatica and F. gigantica) do not take advantage of the host's circulatory system for their transport. Rather, recently ingested larvae actively penetrate the intestinal wall of the host and then migrate through the peritoneum towards the liver.

The life cycle of cestodes (tapeworms) involves definitive and one or more intermediate hosts. If the intermediate host is a mammal – and this may include man as an accidental host – the hooked larva penetrates the gut wall and is distributed throughout the body via the blood and the lymphatic system. In different sites of the intermediate host, it develops into an infective cyst (muscle, peritoneal cavity and brain). The cyst may be ingested with the raw flesh of the intermediate host by the final host (man, dog and cat). In the intestinal tract of the final host, the scolex becomes exposed and attaches to the intestinal mucosa where the tapeworm develops into adult form.

Thus, based on such diversity in helminth parasites and on such diversity in the diseases they cause, one could expect a wide range of different helminth-induced immune responses. Despite these differences, most of these organisms induce very similar immune responses in their host. We can collectively term this reaction as the characteristic immune response to a ‘helminth infection’, keeping in mind that this immune response is not necessarily the only reaction of the host immune system to a specific infection. Immune response to a helminth infection is typified by the profile of cytokines they induce, such as high levels of IL-4, IL-5, IL-10 and IL-13, and also high levels of characteristic antibodies such as IgG1 and IgE, as well as increased numbers of particular cell populations such as eosinophils, goblet cells and mast cells (1). Low T cell proliferative responses to polyclonal stimuli and to specific parasite antigens as well as ‘bystander’ decreased T cell proliferation are frequently observed (2). Two more shared features of helminth infections have recently been identified, including regulatory cell subpopulations such as T regulatory cells (3) and alternatively activated macrophages (AAMφ) (4,5). Noteworthy is that besides experimental infections, these responses are features in human parasitosis caused by helminths.

This review will focus on the role of AAMφ, which have been documented in all three classes of parasitic helminths such as nematodes, trematodes and cestodes. However, they appear to play differential roles according to the type and momentum of a specific infection. In this review, we put together different reports, arguing that AAMφ may attack the parasite, may favour host colonization or may avoid immunopathological damage in the host.

MACROPHAGE DIVERSITY

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Macrophages are dedicated phagocytic cells and are one of the most ubiquitous types of cells in many organs and tissues. They are also versatile cells that are known to play three key roles in the immune response. First, macrophages serve as early detectors for invading pathogens through pattern recognition receptors, such as toll-like receptors and C-type lectins. Second, macrophages function as antigen-presenting cells (APC) which initiate host immune responses. Until recently, the third and final role that macrophages played was as effector cells when they directly kill a pathogen (6). A fourth role has been highlighted by recent reports showing that macrophages can play a role as regulatory and suppressor cells as evidenced in parasitic infections and in tumour-bearing hosts (7,8).

In contrast to 15 years ago, when macrophages were classified only as activated or deactivated macrophages, current advances in molecular immunology and the study of macrophage participation in different pathological conditions in human and mouse models have been useful in discovering that macrophages have many facets. Presently, different sophisticated classifications of macrophages have been proposed. These include a simple dual classification such as classical activation (CAMφ) vs. AAMφ, a concept originally introduced in the early 90s by Gordon's research group who observed a direct in vitro effect of IL-4 on macrophage expression of the mannose receptor (MR) (6). Such a key observation gave rise to a completely new field of study, macrophage polarization, which depends on proinflammatory (also termed M1 macrophages) or anti-inflammatory (also termed M2 macrophages) situations and that at least in mice have been suggested to be strain dependent (9). Besides the CAMφ (M1) and AAMφ (Μ2) subpopulations described below, a more complex but not less interesting classification is that proposed by Mantovani et al. (10). They maintain the use of M1 for macrophages with proinflammatory abilities and use the term M2 in a more generic sense and subdivide the M2 population into three distinct subpopulations according to best defined routes of activation and response of these macrophages. Based on such criteria, M2 macrophages are classified into subpopulations M2a (which reflects the AAMφ); M2b, which are activated by immune complexes and release high levels of IL-10; and M2c, which are induced by IL-10 and represent the original version of deactivated macrophages. This last classification has been proposed mainly based on the type of stimuli that made the macrophage subpopulations distinguishable and, on the other hand, by the type of chemokines that the macrophages release (10).

All of these types of macrophages can be found in a variety of immunological conditions, such as immune responses to intracellular pathogens, parasitic protozoa, tumours, autoimmunity and, of course, in helminthic infections. Recent excellent reviews have addressed the role of macrophages in cancer and in parasitic protozoan infections (7,8,11), but this review is the first to our knowledge that is focused on alternative macrophage activation and responses to all three classes of helminths.

As a matter of convention, we will use the dichotomy CAMφ and AAMφ. Facing such diversity in the states of macrophage activation, we hypothesize that such activation is microenvironment-dependent (including structural and secreted/excreted molecules of the parasites), meaning that macrophages have high plasticity to respond to the changing environment in the host. Thus, macrophages are able to respond to the microbial and cytokine milieu, driving the expression of polarized functional properties. In general, the best characterized subpopulation of macrophages are the CAMφ which are induced by IFN-γ, TNF-α and microbial products such as lipopolysaccharides (LPS). CAMφ can be identified by their high ability to produce proinflammatory cytokines and chemokines such as IL-1β, IL-12, IL-23, TNF-α, and CXCL-9, -10, -11 and -16, while producing low amounts of IL-10; they also produce high levels of reactive oxygen and nitrogen intermediates such as nitric oxide (NO) and reactive oxygen species (ROS) (9,10,12). CAMφ have been identified as central players in mediating resistance against intracellular parasites and tumours. Conversely, AAMφ are generally characterized by low production of IL-1β, IL-12, and IL-23, but with discrete IL-10 production (6). They also are greater producers of urea and sometimes of regulatory cytokines such as TGF-β. AAMφ are frequently associated with polarized Th2-type responses, and indeed most reports agree that AAMφ are IL-4- and IL-13 induced and play a central role in tissue repair (13). In this classification, the pathway of activation plays a critical role and determines the mechanism by which macrophages metabolize the amino acid l-arginine. Activation by IFN-γ and TNF-α in CAMφ favours the production of NO, which is mediated by increasing activity of nitric-oxide synthase 2 (NOS2). In contrast, an increasing arginase-1 (Arg-1) activity is observed in AAMφ by IL-4 and IL-13, favouring l-arginine metabolism towards proline, polyamines and urea production (12). More specific markers for AAMφ have been recently identified from in vivo parasitic infections as well as from mice bearing tumours (14). The most relevant signature markers besides Arg-1 and MR are Fizz1, Ym1, TREM-2, AMCase, mMGL1 and mMGL2 (see Table 1 for abbreviations) (14).

Table 1.  Helminths belonging to phylogenetically separated groups induce AAMφ whose function remains debatable. List of the main molecules reported to be associated with AAMφ on helminth parasitic infections
ParasiteIncreased gene expression of AAMφ markersAPC functionSuppressive activityRole in diseaseReference
  1. Fizz1, found in inflammatory zone 1; AMCase, acidic mammalian chitinase; LOX, lipoxygenase; MR, macrophage mannose receptor; Arg-1, arginase-1; PD, programmed death receptor; PDL, programmed death ligand; mMGL, mouse macrophage galactose-type-C-type lectin, CCR5, CC chemokine receptor 5, ND, not determined; TREM, triggering receptor expressed on myeloid cells.

Nematodes
 Brugia malayiFizz1, Ym1, Arg-1Th2-biasing abilityYes (contact dependent/TGF β-partially dependent)Unknown(4,15–17)
 Litomosoides sigmodontisFizz1, Ym1, Arg-1UnknownYes (contact dependent/TGF-β partially dependent)Unknown(20)
 Nippostrongylus brasiliensisFizz1, Fizz2, Ym1, Arg-1, MMR, AMCase IL-21RUnknownUnknownLung homeostasis after acute injury(18,19,36)
 Heligmosomoides polygyrusFizz1, Ym1, MR, AMCase, IL-4RUnknownUnknownHost protection, arginase-mediated parasite clearance(27)
Trematodes
 Schistosoma mansoniFizz1, Ym1, Arg-1 AMCase, MR, IL-21RTh2-biasing abilityYes (PD/PDL1 pathway dependent)Divergent role: host protection down-modulate Th1-mediated immunopathology and progressive pathology in lung and liver granuloma formation(30,33)
 Fasciola hepaticaFizz1, Ym1, Arg-1UnknownUnknownUnknown(34,35)
Cestodes
 Taenia crassicepsFizz1, Ym1, Arg-1, MR, 12/15 LOX, mMGL, CD23, CCR5, OX40L, SLAM, TREM2Th2-biasing abilityYes (PD1–PDL pathway dependent and ROS partially dependent)May favour parasite installation(5,43,44,63)
 Hymenolepis diminutaFizz1, Ym1, Arg-1UnknownUnknownUnknown(52)
 Echinococcus multilocularisNDDown-regulatedYes (ND)Unknown(51)

There is a growing interest in the role and function of AAMφ, as this subpopulation of macrophages has been associated with a diversity of immunological situations ranging from individuals bearing tumours, where strong suppressive activity has been observed, to parasitic infections where a less defined role has been probed.

ROLE OF AAMφ IN HELMINTHIC INFECTIONS

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Nematodes

Brugia malayi

Filariasis is an important human nematode infection affecting thousands of people around the world. A mouse model of infection with B. malayi has been used in the past few years to understand basic aspects of immunomodulation during filariasis. Intraperitoneal infection of mice with B. malayi adults induces the recruitment of high numbers of F4/80+ macrophages along with a strong Th2-type response in a couple of weeks (15,16). When the peritoneal macrophages isolated by adherence were co-cultured with antigen-specific or naïve polyclonally stimulated T cells, a profound inhibition in the proliferative response was observed. These macrophages displayed high Arg-1 activity instead of NOS2 activity. Further studies performed by the same group showed an up-regulation in these macrophages of two more characteristic genes, Fizz1 and Ym1, considered since then as markers for AAMφ in several nematode infections (4). Similarly, increased IL-10 and TGF-β production in this infection were associated with AAMφ. Such inhibitory activity and gene expression were determined to be IL-4-dependent, given that mice lacking IL-4 were unable to induce these AAMφ, whereas IL-10−/– mice sustained both AAMφ induction and suppressive activity during B. malayi infection (4,15). In this specific type of infection, the AAMφ elicited were named NeMφ, and their ability to suppress T cell proliferative responses was found to be contact-dependent and only partially TGF-β-dependent (16,17). However, molecules involved in the cell-to-cell contact were undefined. Nevertheless, these NeMφ induced by B. malayi are considered to play an anti-inflammatory role at the site of infection.

Litomosoides sigmodontis

Another model to study the immunosuppressive effect of filarial infections has been L. sigmodontis that, in contrast to B. malayi, can follow its natural course of infection in mice. Thus, it was also demonstrated that L. sigmodontis infection induces F4/80+ AAMφ (NeMφ) where Fizz1 and Ym1 were up-regulated at the sites of parasite migration and residence in the pleural cavity. A similar macrophage-dependent suppressive activity as well as a similar pattern of expression of Arg-1, Fizz1 and Ym1 were also detected during L. sigmodontis infection, reminiscent of B. malayi studies (18,19). Again, L. sigmodontis-induced NeMφ suppressive activity was contact-dependent and minimally associated with TGF-β. In contrast, blockade of the IL-10 receptor and CTLA-4 did not have any effect on NeMφ suppressive activity. NeMφ were most often found close to the parasite, and they appear to disseminate to lymph node (LN) only when microfilaraemia exit in the pleural cavity (20). The functional role for AAMφ in filariasis is still not fully clear, but evidently induces suppressive activity.

Nippostrongylus brasiliensis

This parasite has been widely used as a model for intestinal nematode infections. Infection is performed subcutaneously, and as the parasites mature, they migrate and enter the lungs where N. brasiliensis induce strong, polarized Th2-type responses in the lungs and in lung-associated LNs (21). Besides the high levels of IL-4 and IL-13 expressions, other genes were also highly expressed in the lungs of infected mice, such as AMCase, Fizz1 and Ym1, suggesting the presence of AAMφ (Table 1). This set of AAMφ markers has recently been associated with the expression of IL-21R during N. brasiliensis infection, and this receptor was shown to be involved in augmenting AAMφ activity, mainly by increasing IL-4Rα and IL-13Rα expressions. Furthermore, lung fibrosis caused by N. brasiliensis infection was associated with the presence of AAMφ (22), given that mice lacking IL-21R induced less AAMφ and therefore pulmonary fibrosis was reduced. Thus, a strong Th2 response together with the presence of AAMφ is associated with the pathology observed in lungs of N. brasiliensis-infected mice. In contrast, other recent observations indicate that AAMφ expressing Arg-1, Ym1, Fizz1 and MR can be induced in the lungs in the absence of CD4 T cells in response to N. brasiliensis infection (23). In this study, GSL-I+ AAMφ were detected in situ (lungs) as early as 4 days post infection (p.i.) in either severe combined immunodeficiency (SCID) or wild type (WT) mice. Nevertheless, these populations remained just past 8 days p.i. in WT mice which displayed a remarkably fast resolution of both mechanical damage and inflammation caused by N. brasiliensis. Conversely, inflammation and damage in the lungs of SCID mice persisted after 8 days p.i. (23). From these results, two important conclusions can be highlighted. First, AAMφ can be elicited in innate immune responses when Th2-specific responses cannot be found, suggesting that N. brasiliensis may directly induce AAMφ or that an early source of IL-4 from innate cells (e.g. mast cells and NK cells) may be enough to induce AAMφ. Second, AAMφ can also play a role as regulatory cells by avoiding excessive lung inflammation as well as remodelling function. A more recent report showed that AAMφ induction during N. brasiliensis infection is strictly dependent on the STAT6-signalling pathway (24). Together these findings imply a clear IL-4/IL-13-dependency for AAMφ to merge during this nematode infection.

Heligmosomoides polygyrus

This is a natural mouse gastrointestinal nematode parasite. Mice became infected with the L3 infective larvae. These larvae exsheath in the stomach and then, after 36 h, move to the small intestine where they can penetrate the mucosa and migrate down to the muscularis interna where they encyst within the muscular wall. Larvae that reach this state mature and develop to adults to emerge from the cysts into the intestinal lumen (25,26). As much as other classes of helminths, H. polygyrus triggers polarized Th2-type responses and can induce chronic infections. If parasites are eliminated after a primary infection, the Th2 memory response protects the host against re-infection. Intestinal AAMφ have recently been found surrounding developing H. polygyrus larvae following a secondary infection (27). As seen in B. malayi, L. sigmodontis and N. brasiliensis infections, these AAMφ were scarce in STAT6−/– and IL-4−/– mice which displayed higher parasite and egg burdens. When WT mice were depleted of either CD4 cells using a specific antibody in vivo or were depleted of AAMφ by using clodronate-loaded liposomes, a defective worm expulsion was observed in parallel with increased egg recoveries (27). Surprisingly, these data suggested for the first time a protective role for AAMφ in a helminth infection besides the classical involvement of eosinophils. As mentioned above, arginase activity is one of the characteristic features of AAMφ. In this study, when arginase was chemically blocked in resistant mice, an enhanced larval recovery was observed, suggesting a role for arginase in host protective responses against the intestinal phase of H. polygyrus. Until that work, no role for arginase had been associated with protective responses in infectious diseases. Notably, AAMφ in this infection were only detected at the site of infection, as also seen with B. malayi, L. sigmodontis and N. brasiliensis.

Trematodes

Schistosoma mansoni

The mouse model for studying the host–parasite relationship in schistosomiasis has been of great utility to understand mechanisms involved in protection, susceptibility and pathology of this important trematode disease that affects millions of people. Early in the 90s, Stadecker's research group found that macrophages isolated from liver granulomas of S. mansoni-infected mice were able to anergize T cell responses to specific and polyclonal stimuli (28). Granulomas in murine schistosomiasis peak 7 or 8 weeks after infection, a time period in which hosts have developed already dominant Th2-type responses (29). Stadecker also found this suppressive activity was IL-2 reversible and demonstrated that these macrophages were able to drive Th2 responses. Nevertheless, mechanisms participating in both Th2-driven and suppressive activities were undefined. These macrophages isolated from liver granulomas were not defined as AAMφ at that time. However, almost 15 years later, these macrophages have been better defined. It is now known that T cell (both CD4 and CD8) anergy induced by these macrophages during experimental schistosomiasis are cell contact-dependent and a clear participation of the PD-1/PDL pathway has been demonstrated, mainly via selective up-regulation of PD-L1 in these macrophages (30). PD-L1 and PD-L2 are relatively new negative signalling accessory molecules that act through their receptor PD-1 expressed in activated T cells, thereby down-regulating their proliferation (31,32). These suppressive macrophages were also determined to be AAMφ (30). On the other hand, mice lacking the IL-4Rα chain specifically on their macrophages (LysMCreIL-4Rα−/flox mice) succumbed to acute schistosomiasis. This result was associated with the impaired ability of LysMCreIL-4Rα−/flox mice to recruit AAMφ to granuloma tissue despite having a normal Th2-type response. In contrast, elevated numbers of CAMφ were detected in liver granulomas of these mice (33). Therefore, induction of IL-4/IL-13-dependent AAMφ was essential to avoid immunopathological damage and to survive acute schistosomiasis.

Fasciola hepatica

This trematode has a complex life cycle that includes intermediate (snails) and definitive hosts (cattle or human). As with other helminths, F. hepatica induces Th2-type responses. Recently, the induction of markers for AAMφ at early stages of infection has been reported (Table 1). This induction can be mimicked in mice by injecting excreted/secreted products of F. hepatica (34). Notwithstanding that regulatory cytokines were augmented in these macrophages, the immunomodulatory (suppressive or Th2 biasing) activity of this population was not achieved. However, in other experimental model using cattle infection, it was suggested that AAMφ can mask tuberculosis detection by impairing delayed type hypersensitivity (DTH) responses to BCG (35).

Cestodes

Taenia crassiceps

Excellent reviews have recently been published regarding the immune response during trematode and nematode infections (2,21,36). However, the class cestoda has been largely neglected, even though these parasites produce important threatening diseases around the world. The infection of the intermediate hosts by the metacestode stage of Taenia species, and especially T. crassiceps, appears to be a very good model to unveil some of the mechanisms of the host–parasite interplay in cysticercosis. Taenia crassiceps cysticercosis naturally affects rodents and the final hosts are canines. Nevertheless, there are reports demonstrating that immunocompromised humans can develop T. crassiceps cysticercosis (37,38). The metacestode stage of T. crassiceps has the advantage of an asexual budding reproduction (39). This biological phenomenon has been useful in generating long-lasting infections in laboratory mice, where regularly the parasite is inoculated i.p., and after a few weeks, hundreds of macroscopic parasites can be reached from the peritoneal cavity. Additionally, antigenic similarities have been very well established between T. solium and T. crassiceps metacestodes (40). Thus, sera from human patients suffering from neurocysticercosis positively recognize T. crassiceps antigens. After initial infection with T. crassiceps cysticerci, a rapid but transient Th1 response is observed in the host (41), and the immune response is sequentially biased to a Th2 response following a period of a mixed Th1/Th2 response (42). Along with this dynamic immune response, macrophages recruited in the peritoneal cavity change as infection progresses. Peritoneal macrophages (F4/80+) isolated at different times after challenge with T. crassiceps have been used as APC and tested for their ability to regulate Th1/Th2 differentiation. Macrophages from acute infections produced high levels of IL-12 and NO, paralleled with low levels of IL-6 and have the ability to induce strong antigen-specific CD4+ T cell proliferation in response to unrelated antigens (5). In contrast, macrophages from chronic infections produced a different pattern of cytokines and chemokines, associated with a poor ability to induce antigen-specific proliferations in CD4+ T cells. Failure to induce proliferation was not due to deficiencies in the expression of accessory molecules, since MHC-II, CD40 and B7-2 were up-regulated, together with CD23 and CCR5 as infection progressed (5). Besides these molecules, another set of markers has recently been found elevated in the peritoneal macrophages from T. crassiceps-infected mice (Table 1), such as high expression of MR, the C-type lectins (mMGL1 and mMGL2), Arg-1, Fizz1, Ym1 and TREM-2, confirming that these macrophages are alternatively activated (43,44). Macrophages from chronic infections were able to bias CD4+ T cells to produce IL-4, but not IFN-γ, contrary to macrophages from acute infections, just like those described previously in nematode infections. Furthermore, studies using STAT6−/– mice revealed that the STAT6-mediated signalling pathway was essential for the expansion of AAMφ in murine cysticercosis (5,45). More recently, it has been shown that IL-4Rα−/– mice were also unable to induce AAMφ after T. crassiceps infection (14). Together, these studies performed by independent groups agree with the early observation of IL-4 dependency for Brugia and Schistosoma AAMφ induction.

Another striking observation has been the ability of AAMφ isolated from T. crassiceps-infected mice to inhibit the proliferative response of naïve T cells (44). Apparently, this effect involves a cell contact-dependent pathway. Supporting evidence for cell contact-dependent involvement was associated with increased expression of PD-L1 and PD-L2 in AAMφ. The participation of the PD-1 pathway was tested by blocking PD-L1 and PD-L2, or PD-1 by adding mAbs to co-cultures of naïve T cells with AAMφ from T. crassiceps-infected mice. Blockade of the PD-1 pathway significantly reduced AAMφ suppressive activity and therefore T cells proliferated normally. These data indicate that PD-L1 and PD-L2 are directly involved in the cell contact suppressive activity of AAMφ from T. crassiceps-infected mice. Whether this will also be true for the contact-dependent suppression seen in nematode infection is yet to be tested.

AAMφ induced by T. crassiceps infection were also demonstrated to suppress the specific response of CD4+ DO11·10 cells to OVA peptide stimulation when normal macrophages were used as APC. Again, the blockade of PD-1 re-established the peptide-specific proliferative response of CD4+ DO11·10 cells. Therefore, AAMφ can participate as a third party suppressive cell. Similarly, the presence of AAMφ in a DC-mediated mixed lymphocyte reaction was enough to inhibit the response of CD4 cells from a different genetic background (44). Thus, AAMφ induced during T. crassiceps infection suppress immunological events mediated through distinct molecular mechanisms that potentially may induce strong proinflammatory responses. It was also demonstrated that the PD-1/PD-L pathway participates in modulating anti-Taenia-specific cell proliferative response.

Initial support for in vivo AAMφ induction by Taenia glycoproteins has recently been reported (46). Together with thioredoxin from F. hepatica, it seems that helminth-derived molecules can induce these types of cells in wild-type mice; however, the role for IL-4 in the antigen induction of AAMφ needs to be clarified.

Translating these series of results to the immune balance in neurocysticercosis, it is therefore possible that the presence of AAMφ with suppressive activity and low proinflammatory profile may be necessary to turn off possible dangerous inflammatory responses in the brain. In fact, a series of reports suggest that active inflammatory responses in neurocysticercosis leads to pathological symptoms (47), whereas a silent (anti-inflammatory) immune response has been associated with asymptomatic neurocysticercosis (48,49).

Echinococcus multilocularis

Alveolar echinococcosis is a chronic cestode infection caused by the metacestode of E. multilocularis. In experimental conditions, infection is achieved by i.p. inoculation of the metacestodes. Similar to the T. crassiceps model, the early immune response is transiently dominated by a Th1 type, but progress of the infection leads to biased Th2-type responses (50). Macrophages appear to play a familiar role in the host–parasite interface. Macrophages isolated from the peritoneal cavity (close to the parasite) 6 weeks p.i. induced a significant reduction in T cell response to an unrelated antigen (OVA peptide) compared to peritoneal macrophages from naïve mice (51). These E. multilocularis-induced macrophages also suppressed Con-A-stimulated lymphocyte proliferation, in which the effect was cell contact dependent (51), even though previous data sustained that soluble factors (NO) were involved in the low proliferative response during echinococcosis (50). Further experiments are necessary to clarify whether or not macrophages induced by E. multilocularis infection belong to the AAMφ subpopulation and whether the cell contact suppressive activity is PD-1 mediated as observed in both schistosomiasis and cysticercosis.

Hymenolepis diminuta

This tapeworm has been recently used to study the immune response evoked against cestodes at the intestinal level. Infection with H. diminuta in mice rapidly drives mesenteric LN cells to produce IL-10, TGF-β and IL-4. In the intestine of H. diminuta-infected mice, markers were detected for natural regulatory cells as well as markers for AAMφ by RT-PCR (Table 1). These AAMφ arrive at day 8 p.i (52). Although direct regulatory activity was not tested, the authors correlate the appearance of AAMφ with the peak time of worm expulsion, suggesting that AAMφ may participate in protection against this cestode infection.

As noticed here, AAMφ have been consistently identified during infections with all the three classes of helminth parasites. Nonetheless, the definition of what constitutes a macrophage varies from study to study based on the panel of cell surface markers used (Table 2). Likewise, the state of alternative activation has also been defined using a diversity of techniques (Table 2). Together, these data support the idea that the induction of AAMφ is another common feature in helminth infections.

Table 2.  Specific membrane macrophage markers and isolation tissues for AAMφ induced by diverse helminthic infections
ParasiteMacrophage specific markersAAMφ isolation tissueAAMφ characterization techniqueReference
  • LN, lymph node; ND, not determined; PECs, peritoneal exudate cells; PBMC, peripheral blood mononuclear cells; EST, expressing sequence tag; IHC, immunohistochemistry; UQ, urea quantification; WB, Western blot; FC, flow cytometry.

  • a

    Enrichment > 85%;

  • b

    in situ detected.

Nematodes
 Brugia malayiF4/80+Adherent PECs mediastinal and parathymic LNaEST/RT-PCR/WB(4,19)
 Litomosoides sigmodontisF4/80+Thoracic/pleural cavity mediastinal and parathymic LNaRT-PCR(19,20)
 Nippostrongylus brasiliensisF4/80+/CD11b+Lung and small intestinebRT-PCR/IHC/WB(19,22,23)
 Heligmosomoides polygyrusF4/80+Small intestinea,bIHC(27)
Trematodes
 Schistosoma mansoniF4/80+/CD11b+Schistosoma egg-induced liver granulomas and adherencea,bFC/IHC(33)
 Fasciola hepaticaF4/80+/CD14+Adherent PECs and PBMCaRT-PCR/UQ(34,35)
Cestodes
 Taenia crassicepsF4/80+/Mac3+/ CD11b+/CD14+Adherent PECsaRT-PCR/UQ/FC(5,43,44,63)
 Hymenolepis diminutaNDSmall and large intestinebRT-PCR(52)
 Echinococcus multilocularisMac1+/CD11b+Adherent PECsaND(51)

ANOTHER DIVERGENT ROLE FOR AAMφ

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

AAMφ induced by helminth infections may have another role. It is well established that previous helminth infection can modulate the immune response in a ‘bystander’ fashion. Therefore, given that concomitant infections are common in developing countries, secondary infections of nonrelated pathogens such as protozoan parasites or mycobacterium may be facilitated. Many concomitant infections are documented in experimental models as well as in human beings living in endemic areas (36,53). Most of the protozoan parasites and mycobacterium (malaria, trypanosomiasis, leishmaniasis and mycobacterium) share one thing, which is the requirement for macrophage internalization where the pathogens proliferate. Taking this into account, at the time when the helminth parasite has subverted the host immune system and macrophages have reached an alternative state of activation characterized by enhanced phagocytic ability and decreased microbicidal/toxic activities, intracellular pathogens can replicate freely. Some examples are the co-infections Schistosoma/leishmaniasis (54), Litomosoides/leishmaniasis (55), Taenia/leishmaniasis (56), Taenia/trypanosomiasis (57), filaria/malaria (58) or in general helminth/tuberculosis (59). In all cases, AAMφ were unable to fully eliminate the second pathogen. Together these data suggest that previous helminth infections have modulatory effects on the immune response elicited against a second challenge mainly by affecting macrophage activity rather than completely inhibiting Th1-type responses.

On the other hand, many experimental as well as geographical correlations in humans indicate that helminth infections can down-regulate allergic as well as autoimmune inflammatory disorders (60,61). Although these disorders are adaptive immune response dependent, a role for innate immunity is well recognized; hence, macrophages and other APC populations that initiate and condition the adaptive response are critical participants. If a macrophage population is conditioned by the alternative state-inducer microenvironment, polarization of the autoantigen response towards anti-inflammatory effector cells can occur. In addition to their function as Th2-biasing APC, AAMφ posses a suppressor ability and, given that this one is nonspecific, the course of autoimmune and allergic diseases may be less severe. As noted here, one mechanism used by parasite helminths to establish successful infections can explain why the course of aetiologically different (i.e. infectious, autoimmune or allergic) disorders can be altered in helminth-bearing hosts.

CONCLUDING REMARKS

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

We have reviewed here the available evidence from experimental in vivo data suggesting that AAMφ are widely induced by all the three classes of helminths and that they play different roles in those infections. AAMφ can be identified as a subpopulation of macrophages with immunomodulatory activities that can be protective for the host by limiting unwanted exacerbated inflammatory responses. However, they may have a role as effector cells eliminating at least one intestinal helminthic infection. AAMφ induced by helminths can also perform tissue repair and remodelling after infection but, on the other hand, they are part of an immunomodulatory strategy to successfully colonize the host. Experimental evidence continues to support a role for AAMφ in the immunoregulation by diverse helminth parasitic diseases as stated here. Yet, many questions remain unanswered. Why are AAMφ localized close to the parasites most of the time? Can these AAMφ migrate to other LN where a new stimulus is delivered? Presently, there is no clear evidence for AAMφ migration. Do they respond to chemokines? How? Are they refractory to proinflammatory cytokine stimuli, even when they express the right receptors? Until now, AAMφ stimulated with inflammatory cytokines or/and LPS do not secrete the expected molecules (62–64). Do helminth-derived molecules induce AAMφ directly? Is it really strictly necessary for an IL-4-dependent signalling pathway for AAMφ to merge in a helminth infection? Until now, STAT6−/–, IL-4−/– and IL-4R−/– mice have consistently been reported for their inability to induce AAMφin vivo in response to the three different classes of helminths. Can we use AAMφ (transfer them) to treat inflammatory diseases to promote and sustain a Th2-polarized immune response associated with a more favourable anti-inflammatory and host-protective environment?

Deciphering these mechanisms will give us new valuable information to better understand helminth immunomodulation as well as to take advantage of their properties.

ACKNOWLEDGEMENTS

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

This work was supported by DGAPA-UNAM grant #IN208706, Fundación Miguel Alemán A.C., and by grant #59561-CONACYT, and is a portion of the requirements for obtaining the doctoral degree in the postgraduate program in biomedical sciences, Faculty of Medicine, UNAM for J.L.R., who is supported by a fellowship from CONACYT-Mexico.

REFERENCES

  1. Top of page
  2. SUMMARY
  3. PARASITE HELMINTH DIVERSITY
  4. MACROPHAGE DIVERSITY
  5. ROLE OF AAMφ IN HELMINTHIC INFECTIONS
  6. ANOTHER DIVERGENT ROLE FOR AAMφ
  7. CONCLUDING REMARKS
  8. ACKNOWLEDGEMENTS
  9. REFERENCES
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