title: Neutrophil myeloperoxidase regulates T-cell-driven tissue inflammation in mice by inhibiting dendritic cell function.
abstract: Myeloperoxidase (MPO) is important in intracellular microbial killing by neutrophils but extracellularly causes tissue damage. Its role in adaptive immunity and T-cell-mediated diseases is poorly understood. Here, T-cell responses in lymph nodes (LNs) were enhanced by MPO deletion or in vivo inhibition, causing enhanced skin delayed-type hypersensitivity and antigen (Ag)-induced arthritis. Responses of adoptively transferred OT-II T cells were greater in MPO-deficient than wild-type (WT) recipients. MPO, deposited by neutrophils in LNs after Ag injection, interacted with dendritic cells (DCs) in vivo. Culture of murine or human DCs with purified MPO or neutrophil supernatant showed that enzymatically dependent MPO-mediated inhibition of DC activation occurs via MPO-generated reactive intermediates and involves DC Mac-1. Transfer of DCs cultured with WT, but not MPO-deficient, neutrophil supernatant attenuated Ag-specific immunity in vivo. MPO deficiency or in vivo inhibition increased DC activation in LNs after immunization. Studies with DQ-ovalbumin showed that MPO inhibits Ag uptake/processing by DCs. In vivo DC transfer and in vitro studies showed that MPO inhibits DC migration to LNs by reducing their expression of CCR7. Therefore, MPO, via its catalytic activity, inhibits the generation of adaptive immunity by suppressing DC activation, Ag uptake/processing, and migration to LNs to limit pathological tissue inflammation.
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Kim M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Ruth C M
authors.initials: RC
authors.lastname: Muljadi
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Edgtton
authors.forename: Diana S Y
authors.initials: DS
authors.lastname: Tan
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Summers
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*
chemical_list: D009195:Peroxidase