Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation of Monocytes and Reduces IL-1β Secretion by Urate Crystal Stimulated Gout PBMCs

ObjectivesTo compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes.MethodsAcute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU (200μg/mL) stimulated IL-1β secretion was determined by ELISA. Reactive oxygen species (ROS) generation in monocytes was determined fluorometrically. PBMCs were incubated with IL-1RA (250ng/mL) or rhPRG4 (200μg/mL) and bead phagocytosis by monocytes was determined. THP-1 monocytes were treated with MSU crystals ± rhPRG4 and cellular levels of NLRP3 protein, pro-IL-1β, secreted IL-1β, and activities of caspase-1 and protein phosphatase-2A (PP2A) were quantified. The peritoneal influx of inflammatory and anti-inflammatory monocytes and neutrophils in Prg4 deficient mice was studied and the impact of rhPRG4 on immune cell trafficking was assessed.ResultsEnhanced phagocytic activation of gout monocytes under basal conditions (p<0.001) was associated with ROS generation and MSU stimulated IL-1β secretion (p<0.05). rhPRG4 reduced bead phagocytosis by normal and gout monocytes compared to IL-1RA and both treatments were efficacious in reducing IL-1β secretion (p<0.05). rhPRG4 reduced pro-IL-1β content, caspase-1 activity, conversion of pro-IL-1β to mature IL-1β and restored PP2A activity in monocytes (p<0.05). PP2A inhibition reversed rhPRG4’s effects on pro-IL-1β and mature IL-1β in MSU stimulated monocytes. Neutrophils accumulated in peritoneal cavities of Prg4 deficient mice (p<0.01) and rhPRG4 treatment reduced neutrophil accumulation and enhanced anti-inflammatory monocyte influx (p<0.05).ConclusionsMSU phagocytosis was higher in gout monocytes resulting in higher ROS and IL-1β secretion. rhPRG4 reduced monocyte phagocytic activation to a greater extent than IL-1RA and reduced IL-1β secretion. The anti-inflammatory activity of rhPRG4 in monocytes is partially mediated by PP2A, and in vivo, PRG4 plays a role in regulating the trafficking of immune cells into the site of a gout flare.

Download Full-text

Abstract 14: An Anti-inflammatory Proton Sensing-receptor Contributes To Cardiovascular Protection Of Gut Microbiota-derived Metabolites

Hypertension ◽

10.1161/hyp.78.suppl_1.14 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Liang Xie ◽

Rikeish R Muralitharan ◽

Evany Dinakis ◽

Michael E Nakai ◽

Hamdi Jama ◽

...

Keyword(s):

T Cell ◽

Gut Microbiota ◽

Dietary Fibre ◽

Dietary Intervention ◽

Immune Cell ◽

Ang Ii ◽

Direct Role ◽

Cardiovascular Protection ◽

Anti Inflammatory ◽

The Impact

High fibre (HF) diet protects against hypertension via the production of acidic metabolites, e.g. short-chain fatty acids, by the gut microbiota. While these metabolites have a direct role in blood pressure (BP) regulation, their acidic nature may activate proton-sensing receptors, which have anti-inflammatory functions. G-protein coupled receptor 65 (GPR65) is a proton-sensing receptor activated around pH 6.5 and is critical for gut homeostasis. We hypothesized that GPR65 is involved in the cardiovascular protection by dietary fibre. We first measured cecal pH of C57BL/6 (WT) mice after a 7-day dietary intervention with either HF or low fibre (LF) diets (n=6/group). HF diet lowered cecal pH to a level where GPR65 is highly activated, compared to the LF diet (6.5±0.1 vs 7.6±0.1, P<0.001). The impact of pH and GPR65 on T cell production of IFNγ, a pro-inflammatory cytokine, in vitro was measured by flow cytometry. Acidic pH inhibited the production of IFNγ by CD8+ T cells (pH 6.5 vs pH 7.5, P<0.001). Cells lacking GPR65 had higher IFNγ at both pH (P<0.001). To determine if GPR65 is involved in BP regulation by dietary fibre, WT and GPR65 knockout ( Gpr65 -/- ) mice were implanted with minipumps containing angiotensin II (Ang II, 0.5mg/kg/day, 28 days, n=8-9/group) and fed with HF diet. BP, cardiorenal function and immune cell infiltration were measured. Gpr65 -/- mice had higher BP compared to WT mice after 2 weeks (mean arterial pressure ± SEM; WT 79.8±2.4 vs Gpr65 -/- 95.8±1.6mmHg, P<0.001) and 4 weeks of Ang II infusion (WT 92.3±2.4 vs Gpr65 -/- 99.5±1.3, P=0.062). Gpr65 -/- mice developed cardiac (P=0.035) and renal (P=0.025) hypertrophy, and impaired renal natriuretic (P=0.054) and diuretic (P=0.056) function compared to WT mice. This was accompanied by higher macrophage (P=0.009) and γδ T cell (P=0.014) infiltration in the kidneys. In conclusion, our data suggest that pH-sensing by GPR65 contributes to the protection against hypertension by dietary fibre via inflammatory mechanisms. This is a novel mechanism that contributes to BP regulation via the gut microbiota.

Download Full-text

TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1809980116 ◽

2018 ◽

Vol 116 (1) ◽

pp. 211-216 ◽

Cited By ~ 2

Author(s):

Bochra Zidi ◽

Christelle Vincent-Fabert ◽

Laurent Pouyet ◽

Marion Seillier ◽

Amelle Vandevelde ◽

...

Keyword(s):

Oxidative Stress ◽

Bone Marrow ◽

B Cells ◽

B Cell ◽

Immune Cell ◽

B Lymphopoiesis ◽

Hematopoietic Stem ◽

Chronic Oxidative Stress ◽

The Impact ◽

Deficient Mice

Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.

Download Full-text

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽

10.1136/gutjnl-2018-317431 ◽

2019 ◽

Vol 69 (2) ◽

pp. 283-294 ◽

Cited By ~ 32

Author(s):

Min-Soo Kim ◽

Yoonhee Kim ◽

Hyunjung Choi ◽

Woojin Kim ◽

Sumyung Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Neurofibrillary Tangles ◽

Immune Cell ◽

Amyloid Β ◽

Memory Deficits ◽

Faecal Microbiota ◽

Inflammatory Monocytes ◽

The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Download Full-text

Liposomal delivery of azithromycin enhances its immunotherapeutic efficacy and reduces toxicity in myocardial infarction

Scientific Reports ◽

10.1038/s41598-020-73593-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ahmed Al-Darraji ◽

Renée R. Donahue ◽

Himi Tripathi ◽

Hsuan Peng ◽

Bryana M. Levitan ◽

...

Keyword(s):

Myocardial Infarction ◽

Immune Cell ◽

Macrophage Polarization ◽

Significant Shift ◽

Inflammatory Genes ◽

Cardiac Recovery ◽

Inflammatory Monocytes ◽

Acute Myocardial Injury ◽

Anti Inflammatory ◽

Target Effects

Abstract A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug’s efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.

Download Full-text

NAD metabolism fuels human and mouse intestinal inflammation

Gut ◽

10.1136/gutjnl-2017-314241 ◽

2017 ◽

Vol 67 (10) ◽

pp. 1813-1823 ◽

Cited By ~ 27

Author(s):

Romana R Gerner ◽

Victoria Klepsch ◽

Sophie Macheiner ◽

Kathrin Arnhard ◽

Timon E Adolph ◽

...

Keyword(s):

Mononuclear Cells ◽

Intestinal Inflammation ◽

Activated T Cells ◽

Nicotinamide Phosphoribosyltransferase ◽

Nad Metabolism ◽

Macrophage Polarisation ◽

Inflammatory Monocytes ◽

Promising Therapeutic Approach ◽

The Impact

ObjectiveNicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism.DesignWe investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.ResultsFK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1−⁄− mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10.ConclusionOur data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Download Full-text

5952The involvement and interplay of HMGB1 with soluble MD-2 in dilated cardiomyopathy and its impact in immune cell recruitment

European Heart Journal ◽

10.1093/eurheartj/ehz746.0102 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Cited By ~ 1

Author(s):

A Kuemmel ◽

R Feldtmann ◽

A Stohbach ◽

A Riad ◽

B Chamling ◽

...

Keyword(s):

Hospital Admission ◽

Dilated Cardiomyopathy ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Immune Cell ◽

Early Death ◽

Monocyte Adhesion ◽

The Impact ◽

Death Group

Abstract Objective Dilated cardiomyopathy (DCM) is characterized by systolic dysfunction and simultaneous dilatation of the left or both ventricles. Besides other causes, the innate immune system plays a major role in the development and progression of the disease. To uncover links between molecular mechanisms and disease progression our group has focused on the toll like receptor 4 / myeloid differentiation factor-2 (MD-2) system. Purpose We already reported that soluble MD-2 (sMD-2) is a risk factor for survival in patients with DCM. High mobility group box protein 1 (HMGB1) is a potent intrinsic interaction partner of MD-2. In the current study, we quantified HMGB-1 in plasma from patients with DCM at baseline, upon first hospital admission. Furthermore, we studied the impact of different HMGB-1 isoforms on monocyte adhesion in vitro. Methods We included 77 DCM patients divided by median time point of death after first hospital admission into “early death”, “late death” and “alive” group. MD-2 was quantified by means of ELISA. MD-2 and HMGB1 was quantified by means of ELISA. Statistical analysis was performed using a linear regression model. Human umbilical vein endothelial cells (HUVEC; n=6) were treated for 48h with two isoforms of HMGB1 (disulfide (ds) and fully reduced (fr)) alone and in combination with MD-2. Subsequently, those activated HUVEC were incubated with fresh isolated peripheral blood mononuclear cells (PBMCs) for 20 min. Finally, monocyte adhesion was quantified using multicolour FACS. Results At baseline, we found significantly increased sMD-2 level in the “early death” group (591.3±75.5 ng/ml) compared to the “later death” group (369.2±46.5 ng/ml; p=0.015) and the “alive” group (303.2±18.1 ng/ml; p<0.001). Likewise, we could demonstrate significantly increased levels of HMGB1 in the “early death” group (0.93±0.14 ng/ml) compared to the “later death” (0.57±0.17 ng/ml; p=0.04) and the “alive” group (0.49±0.06 ng/ml; p<0.001). In all patients who died during the observation period, sMD-2 and HMGB1 plasma levels showed a positive correlation. In vitro, we could demonstrate a significantly increased monocyte adhesion on HUVECs in the dsHMGB1 and the frHMGB1 group compared to controls (p=0.001; p=0.004). In contrast, the dsHMGB1 MD-2 group showed a significantly decreased monocyte adhesion on HUVECs compared to dsHMGB1 treatment alone (p=0.049). In the frHMGB1 MD-2 group, however, the reduction of the monocyte adhesion was less pronounced and did not reach significance (Fig. 1). Conclusion Our findings give a first hint that the interplay between HMGB1 and MD-2 is particularly involved in the development and progression of DCM. Furthermore, the data suggest that soluble MD-2 is capable of reducing the pro-inflammatory effects of dsHMGB1 but not of frHMGB1

Download Full-text

Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2014-206258 ◽

2015 ◽

Vol 75 (3) ◽

pp. 593-600 ◽

Cited By ~ 39

Author(s):

Maartje C P Cleophas ◽

Tania O Crişan ◽

Heidi Lemmers ◽

Helga Toenhake-Dijkstra ◽

Gianluca Fossati ◽

...

Keyword(s):

Hdac Inhibitor ◽

Histone Deacetylases ◽

Mononuclear Cells ◽

Cytokine Production ◽

Hdac Inhibitors ◽

Class I ◽

Acute Gout ◽

Monosodium Urate ◽

Healthy Donors ◽

Anti Inflammatory

ObjectivesAcute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin (IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.MethodsFreshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.ResultsButyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.ConclusionsIn agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.

Download Full-text

Lipofection with Synthetic mRNA as a Simple Method for T-Cell Immunomonitoring

Viruses ◽

10.3390/v13071232 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1232

Author(s):

Natalia Teresa Jarzebska ◽

Julia Frei ◽

Severin Lauchli ◽

Lars E. French ◽

Emmanuella Guenova ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Mononuclear Cells ◽

Immune Cell ◽

Simple Method ◽

Murine Splenocytes ◽

T Cell Immune Responses ◽

Synthetic Mrna ◽

The Impact

The quantification of T-cell immune responses is crucial for the monitoring of natural and treatment-induced immunity, as well as for the validation of new immunotherapeutic approaches. The present study presents a simple method based on lipofection of synthetic mRNA in mononuclear cells as a method to determine in vitro T-cell responses. We compared several commercially available transfection reagents for their potential to transfect mRNA into human peripheral blood mononuclear cells and murine splenocytes. We also investigated the impact of RNA modifications in improving this method. Our results demonstrate that antigen-specific T-cell immunomonitoring can be easily and quickly performed by simple lipofection of antigen-coding mRNA in complex immune cell populations. Thus, our work discloses a convenient solution for the in vitro monitoring of natural or therapy-induced T-cell immune responses.

Download Full-text

IL-15Rα-Independent IL-15 Signaling in Non-NK Cell-Derived IFNγ Driven Control of Listeria monocytogenes

Frontiers in Immunology ◽

10.3389/fimmu.2021.793918 ◽

2021 ◽

Vol 12 ◽

Author(s):

Madhuparna Nandi ◽

Mitterrand Muamba Moyo ◽

Sakina Orkhis ◽

Jeanne Masunga Faida Mobulakani ◽

Marc-André Limoges ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Immune Cell ◽

Nk Cell ◽

Myeloid Cell ◽

Inflammatory Monocytes ◽

Receptor Chain ◽

Bacterial Uptake ◽

Deficient Mice

Interleukin-15, produced by hematopoietic and parenchymal cells, maintains immune cell homeostasis and facilitates activation of lymphoid and myeloid cell subsets. IL-15 interacts with the ligand-binding receptor chain IL-15Rα during biosynthesis, and the IL-15:IL-15Rα complex is trans-presented to responder cells that express the IL-2/15Rβγc complex to initiate signaling. IL-15-deficient and IL-15Rα-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15Rαβγc complex is considered the functional IL-15 receptor. However, studies on the pathogenic role of IL-15 in inflammatory and autoimmune diseases indicate that IL-15 can signal independently of IL-15Rα via the IL-15Rβγc dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15Rα (partial/distinct signaling) to control Listeria monocytogenes infection. We show that IL-15-deficient mice succumb to infection whereas IL-15Rα-deficient mice clear the pathogen as efficiently as wildtype mice. IL-15-deficient macrophages did not show any defect in bacterial uptake or iNOS expression in vitro. In vivo, IL-15 deficiency impaired the accumulation of inflammatory monocytes in infected spleens without affecting chemokine and pro-inflammatory cytokine production. The inability of IL-15-deficient mice to clear L. monocytogenes results from impaired early IFNγ production, which was not affected in IL-15Rα-deficient mice. Administration of IFNγ partially enabled IL-15-deficient mice to control the infection. Bone marrow chimeras revealed that IL-15 needed for early bacterial control can originate from both hematopoietic and non-hematopoietic cells. Overall, our findings indicate that IL-15-dependent IL-15Rα-independent signaling via the IL-15Rβγc dimeric complex is necessary and sufficient for the induction of IFNγ from sources other than NK/NKT cells to control bacterial pathogens.

Download Full-text

Schistosome immunomodulators

PLoS Pathogens ◽

10.1371/journal.ppat.1010064 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1010064

Author(s):

Sreemoyee Acharya ◽

Akram A. Da’dara ◽

Patrick J. Skelly

Keyword(s):

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Cell Metabolism ◽

Natural Infection ◽

Host Cells ◽

Anionic Polymer ◽

Th2 Response ◽

Anti Inflammatory ◽

The Impact

Schistosomes are long lived, intravascular parasitic platyhelminths that infect >200 million people globally. The molecular mechanisms used by these blood flukes to dampen host immune responses are described in this review. Adult worms express a collection of host-interactive tegumental ectoenzymes that can cleave host signaling molecules such as the “alarmin” ATP (cleaved by SmATPDase1), the platelet activator ADP (SmATPDase1, SmNPP5), and can convert AMP into the anti-inflammatory mediator adenosine (SmAP). SmAP can additionally cleave the lipid immunomodulator sphingosine-1-phosphate and the proinflammatory anionic polymer, polyP. In addition, the worms release a barrage of proteins (e.g., SmCB1, SjHSP70, cyclophilin A) that can impinge on immune cell function. Parasite eggs also release their own immunoregulatory proteins (e.g., IPSE/α1, omega1, SmCKBP) as do invasive cercariae (e.g., Sm16, Sj16). Some schistosome glycans (e.g., LNFPIII, LNnT) and lipids (e.g., Lyso-PS, LPC), produced by several life stages, likewise affect immune cell responses. The parasites not only produce eicosanoids (e.g., PGE2, PGD2—that can be anti-inflammatory) but can also induce host cells to release these metabolites. Finally, the worms release extracellular vesicles (EVs) containing microRNAs, and these too have been shown to skew host cell metabolism. Thus, schistosomes employ an array of biomolecules—protein, lipid, glycan, nucleic acid, and more, to bend host biochemistry to their liking. Many of the listed molecules have been individually shown capable of inducing aspects of the polarized Th2 response seen following infection (with the generation of regulatory T cells (Tregs), regulatory B cells (Bregs) and anti-inflammatory, alternatively activated (M2) macrophages). Precisely how host cells integrate the impact of these myriad parasite products following natural infection is not known. Several of the schistosome immunomodulators described here are in development as novel therapeutics against autoimmune, inflammatory, and other, nonparasitic, diseases.

Download Full-text