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Macrophage origin limits functional plasticity in helminth-bacterial co-infection.

ABSTRACT: Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of M? activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.

SUBMITTER: Ruckerl D

PROVIDER: S-EPMC5364000 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Macrophage origin limits functional plasticity in helminth-bacterial co-infection.

Rückerl Dominik D Campbell Sharon M SM Duncan Sheelagh S Sutherland Tara E TE Jenkins Stephen J SJ Hewitson James P JP Barr Tom A TA Jackson-Jones Lucy H LH Maizels Rick M RM Allen Judith E JE

PLoS pathogens 20170323 3

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activati ...[more]

PMID: 28334040

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Project description:BackgroundMorbidity due to Schistosoma haematobium and hookworm infections is marked in those with intense co-infections by these parasites. The development of a spatial predictive decision-support tool is crucial for targeting the delivery of integrated mass drug administration (MDA) to those most in need. We investigated the co-distribution of S. haematobium and hookworm infection, plus the spatial overlap of infection intensity of both parasites, in Ghana. The aim was to produce maps to assist the planning and evaluation of national parasitic disease control programs.Methodology/principal findingsA national cross-sectional school-based parasitological survey was conducted in Ghana in 2008, using standardized sampling and parasitological methods. Bayesian geostatistical models were built, including a multinomial regression model for S. haematobium and hookworm mono- and co-infections and zero-inflated Poisson regression models for S. haematobium and hookworm infection intensity as measured by egg counts in urine and stool respectively. The resulting infection intensity maps were overlaid to determine the extent of geographical overlap of S. haematobium and hookworm infection intensity. In Ghana, prevalence of S. haematobium mono-infection was 14.4%, hookworm mono-infection was 3.2%, and S. haematobium and hookworm co-infection was 0.7%. Distance to water bodies was negatively associated with S. haematobium and hookworm co-infections, hookworm mono-infections and S. haematobium infection intensity. Land surface temperature was positively associated with hookworm mono-infections and S. haematobium infection intensity. While high-risk (prevalence >10-20%) of co-infection was predicted in an area around Lake Volta, co-intensity was predicted to be highest in foci within that area.Conclusions/significanceOur approach, based on the combination of co-infection and co-intensity maps allows the identification of communities at increased risk of severe morbidity and environmental contamination and provides a platform to evaluate progress of control efforts.

Project description:Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Project description:BackgroundType 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent.ObjectiveWe sought to investigate the role of CYLD in Treg cell function and TH2 cell immune responses under steady-state conditions and during helminth infection.MethodsFoxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays.ResultsTreg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation.ConclusionsOur findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into TH2 cell-like effector cells, which potentiates parasite resistance.

Dataset Information

Macrophage origin limits functional plasticity in helminth-bacterial co-infection.

Publications

Macrophage origin limits functional plasticity in helminth-bacterial co-infection.

Similar Datasets

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