Ongoing exposure to peritoneal dialysis fluid alters resident peritoneal macrophage phenotype and activation propensity

Peritoneal dialysis (PD) is a more continuous alternative to haemodialysis, for patients with chronic kidney disease, with considerable initial benefits for survival, patient independence and healthcare costs. However, long-term PD is associated with significant pathology, negating the positive effects over haemodialysis. Importantly, peritonitis and activation of macrophages is closely associated with disease progression and treatment failure. However, recent advances in macrophage biology suggest opposite functions for macrophages of different cellular origins. While monocyte-derived macrophages promote disease progression in some models of fibrosis, tissue resident macrophages have rather been associated with protective roles. Thus, we aimed to identify the relative contribution of tissue resident macrophages to PD induced inflammation in mice. Unexpectedly, we found an incremental loss of homeostatic characteristics, anti-inflammatory and efferocytic functionality in peritoneal resident macrophages, accompanied by enhanced inflammatory responses to external stimuli. Moreover, presence of glucose degradation products within the dialysis fluid led to markedly enhanced inflammation and almost complete disappearance of tissue resident cells. Thus, alterations in tissue resident macrophages may render long-term PD patients sensitive to developing peritonitis and consequently fibrosis/sclerosis

Taming the neutrophil : Balance between anti‐parasite defence and pathogenesis

Non peer reviewedPublisher PD

The extracellular matrix and the immune system : A mutually dependent relationship

Acknowledgments: We are very grateful to our colleagues at the Wellcome Centre for Cell-Matrix Research and the Lydia Becker Institute for Immunology and Inflammation for many stimulating discussions. We would especially like to thank A. Day, D. Thornton, R. Lennon, A. MacDonald, and T. Hardingham and the anonymous referees for critical review of the manuscript. Figures have been drawn in BioRender. Funding: This work was supported by MRC-UK grant MR/V011235/1 (J.E.A.) and Wellcome Trust grants 106898/A/15/Z (J.E.A.), 218570/Z/19/Z (D.P.D.), and 203128/A/16/Z (T.E.S., D.P.D., and J.E.A.).Peer reviewedPostprin

Magnitude effects for experienced rewards at short delays in the escalating interest task

A first-person shooter video game was adapted for the study of choice between smaller sooner and larger later rewards. Participants chose when to fire a weapon that increased in damage potential over a short interval. When the delay to maximum damage was shorter (5 – 8 s), people showed greater sensitivity to the consequences of their choices than when the delay was longer (17 – 20 s). Participants also evidenced a magnitude effect by waiting proportionally longer when the damage magnitudes were doubled for all rewards. The experiment replicated the standard magnitude effect with this new video game preparation over time scales similar to those typically used in nonhuman animal studies and without complications due to satiation or cost

The magnitude of airway remodeling is not altered by distinct allergic inflammatory responses in BALB/c versus C57BL/6 mice but matrix composition differs

From Wiley via Jisc Publications RouterHistory: received 2020-10-20, rev-recd 2021-01-23, accepted 2021-02-11, pub-electronic 2021-03-19, pub-print 2021-07Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/K01207X/1, MR/P02615X/1Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269; Grant(s): 106898/A/15/ZFunder: Asthma UK; Id: http://dx.doi.org/10.13039/501100000362; Grant(s): MRFAUK‐2015‐302Funder: Medical Research Foundation UK; Grant(s): MRFAUK‐2015‐302Abstract: Allergic airway inflammation is heterogeneous with variability in immune phenotypes observed across asthmatic patients. Inflammation has been thought to directly contribute to airway remodeling in asthma, but clinical data suggest that neutralizing type 2 cytokines does not necessarily alter disease pathogenesis. Here, we utilized C57BL/6 and BALB/c mice to investigate the development of allergic airway inflammation and remodeling. Exposure to an allergen cocktail for up to 8 weeks led to type 2 and type 17 inflammation, characterized by airway eosinophilia and neutrophilia and increased expression of chitinase‐like proteins in both C57BL/6 and BALB/c mice. However, BALB/c mice developed much greater inflammatory responses than C57BL/6 mice, effects possibly explained by a failure to induce pathways that regulate and maintain T‐cell activation in C57BL/6 mice, as shown by whole lung RNA transcript analysis. Allergen administration resulted in a similar degree of airway remodeling between mouse strains but with differences in collagen subtype composition. Increased collagen III was observed around the airways of C57BL/6 but not BALB/c mice while allergen‐induced loss of basement membrane collagen IV was only observed in BALB/c mice. This study highlights a model of type 2/type 17 airway inflammation in mice whereby development of airway remodeling can occur in both BALB/c and C57BL/6 mice despite differences in immune response dynamics between strains. Importantly, compositional changes in the extracellular matrix between genetic strains of mice may help us better understand the relationships between lung function, remodeling and airway inflammation

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type-2 immune response to nematode infection

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifng signature in Il17a-KO mice confirmed by enhanced IFNγ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type-2 response was established, IL-17A limited the magnitude of the type-2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFNγ but subsequently limits excessive type-2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines

IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

Acknowledgements This work was supported by the Wellcome Trust (203128/Z/16/Z, 110126/Z/ 15/Z, and 106898/A/15/Z) and the Medical Research Council UK (MR/ K01207X/2). TE Sutherland was supported by Medical Research Founda- tion UK joint funding with Asthma UK (MRFAUK-2015-302). We thank Andrew McKenzie (Cambridge) for providing the Il13 tm3.1Anjm mice. We further thank the Flow Cytometry, Bioimaging, Genomic Technologies, BioMS, and Bio- logical Services core facilities at the University of Manchester.Peer reviewedPublisher PD

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type-2 immune response to nematode infection

From Springer Nature via Jisc Publications RouterHistory: received 2020-04-17, rev-recd 2020-05-21, accepted 2020-06-09, registration 2020-06-19, pub-electronic 2020-07-07, online 2020-07-07, pub-print 2020-11Publication status: PublishedAbstract: Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifng signature in Il17a-KO mice confirmed by enhanced IFNγ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type-2 response was established, IL-17A limited the magnitude of the type-2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFNγ but subsequently limits excessive type-2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines

A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

From Hindawi via Jisc Publications RouterHistory: publication-year 2021, received 2021-09-02, accepted 2021-10-25, pub-print 2021-11-25, archival-date 2021-11-25Publication status: PublishedFunder: Coronado BiosciencesFunder: FAZIT Stiftung; doi: http://dx.doi.org/10.13039/501100003099Funder: Deutsche Forschungsgemeinschaft; doi: http://dx.doi.org/10.13039/501100001659; Grant(s): GRK 1673Immunomodulation of airway hyperreactivity by excretory-secretory (ES) products of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELMα+ interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts’ own chitinase activity in the inflamed lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed high similarities to mouse acidic mammalian chitinase (AMCase) but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease-ameliorating effect of the helminth-derived chitinase on allergic lung inflammation

IL-13 is a driver of COVID-19 severity

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2–infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti–IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology