Trichinella spiralis-induced mastocytosis and erythropoiesis are simultaneously supported by a bipotent mast cell/erythrocyte precursor cell.

Anti-helminth responses require robust type 2 cytokine production that simultaneously promotes worm expulsion and initiates the resolution of helminth-induced wounds and hemorrhaging. However, how infection-induced changes in hematopoiesis contribute to these seemingly distinct processes remains unknown. Recent studies have suggested the existence of a hematopoietic progenitor with dual mast cell-erythrocyte potential. Nonetheless, whether and how these progenitors contribute to host protection during an active infection remains to be defined. Here, we employed single cell RNA-sequencing and identified that the metabolic enzyme, carbonic anhydrase (Car) 1 marks a predefined bone marrow-resident hematopoietic progenitor cell (HPC) population. Next, we generated a Car1-reporter mouse model and found that Car1-GFP positive progenitors represent bipotent mast cell/erythrocyte precursors. Finally, we show that Car1-expressing HPCs simultaneously support mast cell and erythrocyte responses during Trichinella spiralis infection. Collectively, these data suggest that mast cell/erythrocyte precursors are mobilized to promote type 2 cytokine responses and alleviate helminth-induced blood loss, developmentally linking these processes. Collectively, these studies reveal unappreciated hematopoietic events initiated by the host to combat helminth parasites and provide insight into the evolutionary pressure that may have shaped the developmental relationship between mast cells and erythrocytes.

Toxoplasma gondii causes increased ICAM-1 and serotonin expression in the jejunum of rats 12 h after infection.

OBJECTIVE: To analyze the remodeling dynamics of total collagen, type I and III, the expression of ICAM-1 and 5-HT in the jejunum of rats. METHODS: Twenty-eight Wistar rats were randomly assigned to two experimental groups: the control group (CG, n = 7) and the infected group (receiving 5,000 sporulated T. gondii oocysts - ME49 strain, genotype II, n = 21). Seven infected rats each at 6 (G6), 12 (G12), and 24 (G24) hours post infection were sacrificed and segments of jejunum were collected for standard histological, histochemical, and immunohistochemistry processing techniques. RESULTS: The infection promoted ICAM-1 and 5-HT expression, type III collagen, and total mast cell increases. However, it also caused a reduction in the area occupied by type I collagen fibers, and in submucosa thickness, and caused ganglion and peri-ganglion alterations. CONCLUSION: The structural damage caused by toxoplasmic infection is intense during the first 24 h post inoculation. At peak dissemination, from 12 to 24 h, there is an increase in ICAM-1 and 5-HT expression, with intense migration of mast cells to the site of infection. There was also a reduction in submucosa thickness, and an effective loss of extracellular matrix (ECM) organization, which included changes in the dynamics of type I and III total collagen deposition.

BLT1-mediated O-GlcNAcylation is required for NOX2-dependent migration, exocytotic degranulation and IL-8 release of human mast cell induced by Trichomonas vaginalis-secreted LTB4.

Trichomonas vaginalis is a sexually-transmitted protozoan parasite that causes vaginitis and cervicitis. Although mast cell activation is important for provoking tissue inflammation during infection with parasites, information regarding the signaling mechanisms in mast cell activation and T. vaginalis infection is limited. O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of serine and threonine residues that functions as a critical regulator of intracellular signaling, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). We investigated if O-GlcNAcylation was associated with mast cell activation induced by T. vaginalis-derived secretory products (TvSP). Modified TvSP collected from live trichomonads treated with the 5-lipooxygenase inhibitor AA861 inhibited migration of mast cells. This result suggested that mast cell migration was caused by stimulation of T. vaginalis-secreted leukotrienes. Using the BLT1 antagonist U75302 or BLT1 siRNA, we found that migration of mast cells was evoked via LTB4 receptor (BLT1). Furthermore, TvSP induced protein O-GlcNAcylation and OGT expression in HMC-1 cells, which was prevented by transfection with BLT1 siRNA. TvSP-induced migration, ROS generation, CD63 expression and IL-8 release were significantly suppressed by pretreatment with OGT inhibitor ST045849 or OGT siRNA. These results suggested that BLT1-mediated OGlcNAcylation was important for mast cell activation during trichomoniasis.

Mast Cells and Serotonin Synthesis Modulate Chagas Disease in the Colon: Clinical and Experimental Evidence.

BACKGROUND: Trypanosoma cruzi (T. cruzi) infects millions of Latin Americans each year and can induce chagasic megacolon. Little is known about how serotonin (5-HT) modulates this condition. Aim We investigated whether 5-HT synthesis alters T. cruzi infection in the colon. MATERIALS AND METHODS: Forty-eight paraffin-embedded samples from normal colon and chagasic megacolon were histopathologically analyzed (173/2009). Tryptophan hydroxylase 1 (Tph1) knockout (KO) mice and c-KitW-sh mice underwent T. cruzi infection together with their wild-type counterparts. Also, mice underwent different drug treatments (16.1.1064.60.3). RESULTS: In both humans and experimental mouse models, the serotonergic system was activated by T. cruzi infection (p < 0.05). While treating Tph1KO mice with 5-HT did not significantly increase parasitemia in the colon (p > 0.05), rescuing its synthesis promoted trypanosomiasis (p < 0.01). T. cruzi-related 5-HT release (p < 0.05) seemed not only to increase inflammatory signaling, but also to enlarge the pericryptal macrophage and mast cell populations (p < 0.01). Knocking out mast cells reduced trypanosomiasis (p < 0.01), although it did not further alter the neuroendocrine cell number and Tph1 expression (p > 0.05). Further experimentation revealed that pharmacologically inhibiting mast cell activity reduced colonic infection (p < 0.01). A similar finding was achieved when 5-HT synthesis was blocked in c-KitW-sh mice (p > 0.05). However, inhibiting mast cell activity in Tph1KO mice increased colonic trypanosomiasis (p < 0.01). CONCLUSION: We show that mast cells may modulate the T. cruzi-related increase of 5-HT synthesis in the intestinal colon.

Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection.

Type-2-cell-mediated immune responses play a critical role in mediating both host-resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology.

Marked subcutaneous mast cell and eosinophilic infiltration associated with the presence of multiple Dirofilaria repens microfilariae in 4 dogs.

Dirofilaria repens is a parasitic nematode in the subcutaneous tissue of carnivores, including dogs and cats, transmitted by mosquitoes. Human beings may be accidental hosts. Infection of a dog with D repens was first reported in Palestine in 1934, and 2 additional cases were reported in dogs in Israel to date. This report describes D repens infection in 4 dogs in Israel that presented with subcutaneous masses, which were cytologically characterized by marked mast cell and eosinophil infiltration. In 3 cases, multiple microfilariae were present in the lesions; rare microfilariae were present in the 4th case. In all 4 dogs, PCR of fine-needle aspirates from the lesions were positive for D repens. The mast cells observed in all lesions were uniform and highly granulated, and with the presence of the microfilariae, a mast cell tumor was considered less likely. This report suggests that D repens infection-associated subcutaneous lesions, characterized cytologically by massive mast cell and eosinophil infiltration, should be considered a differential diagnosis for mast cell tumor, especially in geographic locations endemic for this nematode. Notably, all 4 dogs were infected with D repens despite a routine prophylactic doramectin therapy administered every 3 months, probably due to the relatively long time interval between treatments.

Serglycin proteoglycans limit enteropathy in Trichinella spiralis-infected mice.

BACKGROUND: Serglycin proteoglycans are essential for maturation of secretory granules and for the correct granular storage of cationic proteases in hematopoietic cells, e.g. mast cells. However, little is known about the in vivo functions of serglycin proteoglycans during infection. Here we investigated the potential role of serglycin proteoglycans in host defense after infection with the nematode Trichinella spiralis. RESULTS: Twelve days post infection lack of serglycin proteoglycans caused significantly increased enteropathy. The serglycin-deficient mice showed significantly increased intestinal worm burden, reduced recruitment of mast cells to the intestinal crypts, decreased levels of the mast cell proteases MCPT5 and MCPT6 in intestinal tissue, decreased serum levels of TNF-α, IL-1ß, IL-10 and IL-13, increased levels of IL-4 and total IgE in serum, and increased intestinal levels of the neutrophil markers myeloperoxidase and elastase, as compared to wild type mice. At five weeks post infection, increased larvae burden and inflammation were seen in the muscle tissue of the serglycin-deficient mice. CONCLUSIONS: Our results demonstrate that the serglycin-deficient mice were more susceptible to T. spiralis infection and displayed an unbalanced immune response compared to wild type mice. These findings point to an essential regulatory role of serglycin proteoglycans in immunity.

The skin is an important bulwark of acquired immunity against intestinal helminths.

Once animals have experienced a helminthic infection, they often show stronger protective immunity against subsequent infections. Although helminthic infections are well known to elicit Th2-type immune responses, it remains ill-defined where and how acquired protection is executed. Here we show that skin-invading larvae of the intestinal helminth Nippostrongylus brasiliensis are surrounded by skin-infiltrating cells and are prevented from migrating out of infected skin during the second but not the first infection. B cell- or IgE receptor FcεRI-deficient mice showed impaired larval trapping in the skin. Selective ablation of basophils, but not mast cells, abolished the larval trapping, leading to increased worm burden in the lung and hence severe lung injury. Skin-infiltrating basophils produced IL-4 that in turn promoted the generation of M2-type macrophages, leading to the larval trapping in the skin through arginase-1 production. Basophils had no apparent contribution to worm expulsion from the intestine. This study thus reveals a novel mode of acquired antihelminth immunity, in which IgE-armed basophils mediate skin trapping of larvae, thereby limiting lung injury caused by larval migration.

IgG and IgE collaboratively accelerate expulsion of Strongyloides venezuelensis in a primary infection.

The host deploys a subset of immune responses to expel helminths, which differs depending on the nature of the helminth. Strongyloides venezuelensis, a counterpart of the human pathogen S. stercoralis, naturally infects rodents and has been used as an experimental model. Here we show that induction of immunoglobulin G (IgG) and IgE is a prerequisite for rapid expulsion of S. venezuelensis during a primary infection. Activation-induced cytidine deaminase-deficient (AID(-/-)) mice, which lack the ability to switch IgM to other isotypes, normally developed T-helper 2 (Th2) cells and intestinal mastocytosis after infection with S. venezuelensis. Although AID(-/-) mice expelled Nippostrongylus brasiliensis normally, they required a much longer period to expel S. venezuelensis than wild-type (WT) mice. Adoptive transfers of immune sera from S. venezuelensis-infected but not N. brasiliensis-infected mice restored the ability of AID(-/-) mice to promptly expel S. venezuelensis. Immune serum-derived IgG and IgE induced worm expulsion via Fc γ receptor III (FcγRIII) and Fc ε receptor I (FcεRI), respectively, and a mixture of IgG and IgE showed collaborative effects. Whereas FcγRIII(-/-) mice or FcεRIα(-/-) mice normally could expel S. venezuelensis, FcγRIII(-/-) mice, when their IgE was neutralized by anti-IgE, or FcεRIα(-/-) mice, when their IgG binding to FcγRIII was blocked by anti-FcγRIII, showed a markedly reduced ability to expel S. venezuelensis. These data reveal that IgG and IgE play redundant roles but act in concert to accelerate S. venezuelensis expulsion. Mast cell-deficient mice, even those equipped with immune serum-derived IgG or IgE, failed to expel S. venezuelensis promptly, suggesting that mast cells are cellular targets of IgG and IgE.

Mast cells recruited to mesenteric lymph nodes during helminth infection remain hypogranular and produce IL-4 and IL-6.

Mast cells (MC) and basophils share expression of the high-affinity receptor for IgE (FcεRI) but can be distinguished by their divergent expression of KIT and CD49b. In BALB/c mice, MC lineage cells expressing high levels of FcεRI by flow cytometry were seen only in bone marrow whereas those expressing intermediate levels of FcεRI were present in bone marrow and spleen of naive mice and in mesenteric lymph nodes (mLN) of Trichinella spiralis-infected mice. These FcεRI(+)KIT(+)CD49b(-) cells had a membrane phenotype similar to i.p. connective tissue-type MC, but were smaller and hypogranular by flow cytometry forward and side scatter profiles, respectively. Consistent with this, they lacked the prominent secretory granules identified by histochemistry and immunodetection for the MC-specific granule proteases that are readily seen in mature jejunal mucosal MC that also are induced by the infection and present at the same time. The concentration of these MC lineage cells in mLN determined by flow cytometry was comparable to that of MC progenitors (MCp) measured by limiting dilution and clonal expansion with maturation. We observed upregulation of IL-4 transcription by MCp in mLN and spleens of helminth-infected 4get mice, and we demonstrated by intracellular cytokine staining production of IL-4 and IL-6 by the mLN MCp in helminth-infected mice. Furthermore, treatment of helminth-infected mice with anti-FcεRI mAb, a protocol known to deplete basophils, also depleted mLN MCp. Thus, this study identifies a hypogranular subset of MCp recruited to mLN by helminth infection that may be an important unrecognized source of cytokines.

Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity.

Myeloid-derived suppressor cells (MDSCs) are primarily recognized for their immunosuppressive properties in malignant disease. However, their interaction with other innate immune cells and their regulation of immune responses, such as in parasitic infection, necessitate further characterization. We used our previously published mouse model of MDSC accumulation to examine the immunoregulatory role of MDSCs in B16 melanoma metastasis and Nippostrongylus brasiliensis infection. In this study, we demonstrate that the activity of MDSCs is dependent on the immune stimuli and subset induced. Monocytic MDSCs predictably suppressed antitumor immune responses but granulocytic MDSCs surprisingly enhanced the clearance of N. brasiliensis infection. Intriguingly, both results were dependent on MDSC interaction with mast cells (MCs), as demonstrated by adoptive-transfer studies in MC-deficient (Kit(Wsh)(/)(Wsh)) mice. These findings were further supported by ex vivo cocultures of MCs and MDSCs, indicating a synergistic increase in cytokine production. Thus, MCs can enhance both immunosuppressive and immunosupportive functions of MDSCs.

Parasitic infection improves survival from septic peritonitis by enhancing mast cell responses to bacteria in mice.

Mammals are serially infected with a variety of microorganisms, including bacteria and parasites. Each infection reprograms the immune system's responses to re-exposure and potentially alters responses to first-time infection by different microorganisms. To examine whether infection with a metazoan parasite modulates host responses to subsequent bacterial infection, mice were infected with the hookworm-like intestinal nematode Nippostrongylus brasiliensis, followed in 2-4 weeks by peritoneal injection of the pathogenic bacterium Klebsiella pneumoniae. Survival from Klebsiella peritonitis two weeks after parasite infection was better in Nippostrongylus-infected animals than in unparasitized mice, with Nippostrongylus-infected mice having fewer peritoneal bacteria, more neutrophils, and higher levels of protective interleukin 6. The improved survival of Nippostrongylus-infected mice depends on IL-4 because the survival benefit is lost in mice lacking IL-4. Because mast cells protect mice from Klebsiella peritonitis, we examined responses in mast cell-deficient Kit(W-sh)/Kit(W-sh) mice, in which parasitosis failed to improve survival from Klebsiella peritonitis. However, adoptive transfer of cultured mast cells to Kit(W-sh)/Kit(W-sh) mice restored survival benefits of parasitosis. These results show that recent infection with Nippostrongylus brasiliensis protects mice from Klebsiella peritonitis by modulating mast cell contributions to host defense, and suggest more generally that parasitosis can yield survival advantages to a bacterially infected host.

Mast cell function and death in Trypanosoma cruzi infection.

Although the roles of mast cells (MCs) are essential in many inflammatory and fibrotic diseases, their role in Trypanosoma cruzi-induced cardiomyopathy is unexplored. In this study, we treated infected CBA mice with cromolyn, an MC stabilizer, and observed much greater parasitemia and interferon-γ levels, higher mortality, myocarditis, and cardiac damage. Although these data show that MCs are important in controlling acute infection, we observed MC apoptosis in the cardiac tissue and peritoneal cavity of untreated mice. In the heart, pericardial mucosal MC die, perhaps because of reduced amounts of local stem cell factor. Using RT-PCR in purified cardiac MCs, we observed that infection induced transcription of P2X(7) receptor and Fas, two molecules reportedly involved in cell death and inflammatory regulation. In gld/gld mice (FasL(-/-)), apoptosis of cardiac, but not peritoneal, MCs was decreased. Conversely, infection of P2X(7)(-/-) mice led to reduced peritoneal, but not cardiac, MC death. These data illustrate the immunomodulatory role played by MCs in T. cruzi infection and the complexity of molecular interactions that control inflammatory pathways in different tissues and compartments.

Evidence for eosinophil recruitment, leukotriene B4 production and mast cell hyperplasia following Toxocara canis infection in rats

It is well known that eosinophilia is a key pathogenetic component of toxocariasis. The objective of the present study was to determine if there is an association between peritoneal and blood eosinophil influx, mast cell hyperplasia and leukotriene B4 (LTB4) production after Toxocara canis infection. Oral inoculation of 56-day-old Wistar rats (N = 5-7 per group) with 1000 embryonated eggs containing third-stage (L3) T. canis larvae led to a robust accumulation of total leukocytes in blood beginning on day 3 and peaking on day 18, mainly characterized by eosinophils and accompanied by higher serum LTB4 levels. At that time, we also noted increased eosinophil numbers in the peritoneal cavity. In addition, we observed increased peritoneal mast cell number in the peritoneal cavity, which correlated with the time course of eosinophilia during toxocariasis. We also demonstrated that mast cell hyperplasia in the intestines and lungs began soon after the T. canis larvae migrated to these compartments, reaching maximal levels on day 24, which correlated with the complete elimination of the parasite. Therefore, mast cells appear to be involved in peritoneal and blood eosinophil infiltration through an LTB4-dependent mechanism following T. canis infection in rats. Our data also demonstrate a tight association between larval migratory stages and intestinal and pulmonary mast cell hyperplasia in the toxocariasis model.

Histamine and TNF-alpha release by rat peritoneal mast cells stimulated with Trichomonas vaginalis.

Mast cells have been reported to be predominant in the vaginal smears of patients infected with T. vaginalis. In this study, we investigated whether T. vaginalis could induce mast cells to migrate and to produce TNF-alpha and histamine. Rat peritoneal mast cells (RPMC), a primary mast cell, were used for the study. T. vaginalis induced an increase in chemotactic migration of the mast cells toward excretory and secretory product (ESP) of T. vaginalis, and the mast cells activated with T. vaginalis showed an increased release of histamine and TNF-alpha. Therefore, mast cells may be involved in the inflammatory response caused by T. vaginalis.

Intestinal smooth muscle cells locally enhance stem cell factor (SCF) production against gastrointestinal nematode infections.

Smooth muscle cells can produce stem cell factor (SCF) in the normal state for the preservation of mast cells, but it is still unknown whether smooth muscle cells can enhance SCF production in response to the pathological stimuli. The present study showed that smooth muscle cells in mast cell-increased regions around worm cysts of intestinal nematodes significantly enhanced SCF gene expression compared with mast cell non-increased regions in same sample. SCF gene expression in mast cell non-increased regions in nematode-infected mice showed almost the same level as in non-infected control groups. These results indicate that smooth muscle cells can locally enhance SCF gene expression, and may have a role in local immunological reactions as growth factor-producing cells.

Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine.

Notch receptor-mediated signaling is involved in the developmental process and functional modulation of lymphocytes, as well as in mast cell differentiation. Here, we investigated whether Notch signaling is required for antipathogen host defense regulated by mast cells. Mast cells were rarely found in the small intestine of wild-type C57BL/6 mice but accumulated abnormally in the lamina propria of the small-intestinal mucosa of the Notch2-conditional knockout mice in naive status. When transplanted into mast cell-deficient W(sh)/W(sh) mice, Notch2-null bone marrow-derived mast cells were rarely found within the epithelial layer but abnormally localized to the lamina propria, whereas control bone marrow-derived mast cells were mainly found within the epithelial layer. After the infection of Notch2 knockout and control mice with L3 larvae of Strongyloides venezuelensis, the abundant number of mast cells was rapidly mobilized to the epithelial layer in the control mice. In contrast, mast cells were massively accumulated in the lamina propria of the small intestinal mucosa in Notch2-conditional knockout mice, accompanied by impaired eradication of Strongyloides venezuelensis. These findings indicate that cell-autonomous Notch2 signaling in mast cells is required for proper localization of intestinal mast cells and further imply a critical role of Notch signaling in the host-pathogen interface in the small intestine.

Giardia lamblia: interleukin 6 and tumor necrosis factor-alpha release from mast cells induced through an Ig-independent pathway.

Giardia lamblia is a common cause of both acute and chronic diarrheal disease in humans worldwide. It has been shown that mast cells, IL-6 and TNF-alpha are substantially involved in the early control of G. lamblia infection in mice. However, no studies have yet been reported concerning the interaction between mast cell and Giardia, as well as the mast cells mediators generated in response to Giardia infection. In this study we demonstrated the direct activation of mast cells by G. lamblia live trophozoites or trophozoite-derived antigens followed by an increase in tryptase expression and a significant release of the preformed mediator histamine. In addition, parasite derived antigens increased TNF-alpha and de novo synthesized cytokine IL-6, at the mRNA and protein level. These results strongly suggest that mast cells might be an important source not only of IL-6 but also of TNF-alpha during Giardia infection, playing an important role in the outcome of the infection.

Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes.

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world. However, this increase has not been mirrored in developing countries, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

Effect of intestinal inflammation on the cell-specific expression of somatostatin receptor subtypes in the murine ileum.

Despite our knowledge of somatostatin (SOM) in gastrointestinal functions, little information is available on the SOM receptors (SSTRs) mediating these effects. This study focussed on the expression of SSTRs in non-inflamed and Schistosoma mansoni-infected murine ileum using immunocytochemistry, reverse transcriptase (RT)-PCR and quantitative real time RT-PCR (qPCR). In the non-inflamed ileum, SSTRs showed a widespread, cell-type specific expression pattern. For instance, SSTR2A immunoreactivity was detected in a minor population of submucous but not myenteric glial cells. In the inflamed ileum, significant changes in the expression pattern of SSTRs occurred, with SSTR1 and SSTR3 expression on mucosal mast cells (MMCs) and mucosal nerve fibres. SSTR4-immunoreactive nerve fibres were detected in granulomas and the lamina propria. qPCR experiments indicated significantly increased mRNA levels for SOM, SSTR1 and SSTR3 in inflamed ileum. This study reveals that SSTRs are expressed in specific cell types in murine ileum. Expression of SSTR1 and SSTR3 on MMCs and increased density of SOM-expressing nerve fibres in the lamina propria during inflammation, support the hypothesis that SOM is implicated in the physiological control of MMCs during intestinal inflammation. Evidence is provided that in mouse mainly SSTR1, SSTR3 and SSTR4 are involved in the somatostatinergic inflammatory effects during intestinal schistosomiasis.