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1.
Nat Commun ; 13(1): 4658, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945238

RESUMO

The mechanisms linking systemic infection to hyperinflammation and immune dysfunction in sepsis are poorly understood. Extracellular histones promote sepsis pathology, but their source and mechanism of action remain unclear. Here, we show that by controlling fungi and bacteria captured by splenic macrophages, neutrophil-derived myeloperoxidase attenuates sepsis by suppressing histone release. In systemic candidiasis, microbial capture via the phagocytic receptor SIGNR1 neutralizes myeloperoxidase by facilitating marginal zone infiltration and T cell death-dependent histone release. Histones and hyphae induce cytokines in adjacent CD169 macrophages including G-CSF that selectively depletes mature Ly6Ghigh neutrophils by shortening their lifespan in favour of immature Ly6Glow neutrophils with a defective oxidative burst. In sepsis patient plasma, these mediators shorten mature neutrophil lifespan and correlate with neutrophil mortality markers. Consequently, high G-CSF levels and neutrophil lifespan shortening activity are associated with sepsis patient mortality. Hence, by exploiting phagocytic receptors, pathogens degrade innate and adaptive immunity through the detrimental impact of downstream effectors on neutrophil lifespan.


Assuntos
Neutrófilos , Sepse , Fator Estimulador de Colônias de Granulócitos/metabolismo , Histonas/metabolismo , Humanos , Longevidade , Macrófagos/metabolismo , Peroxidase/metabolismo , Linfócitos T/metabolismo
2.
Cell Rep ; 31(5): 107602, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32375035

RESUMO

Neutrophil extracellular traps (NETs) promote atherosclerosis by inducing proinflammatory cytokines, but the underlying mechanism remains unknown. NET DNA is immunogenic, but given the cytotoxicity of NET histones, it is unclear how it activates cells without killing them. Here, we show that histones, DNA, citrullination, and fragmentation synergize to drive inflammation below the histone cytotoxicity threshold. At low concentrations, nucleosomes induce cytokines, but high concentrations kill cells before cytokines are produced. The synergy between histones and DNA is critical for sub-lethal signaling and relies on distinct roles for histones and DNA. Histones bind and activate TLR4, whereas DNA recruits TLR4 to histone-containing endosomes. Citrullination is dispensable for NETosis but potentiates histone-mediated signaling. Consistently, chromatin blockade or PAD4 deficiency reduces atherosclerosis. Inflammation is also reduced in infected mice expressing GFP-tagged histones that block TLR4 binding. Thus, chromatin promotes inflammation in sterile disease and infection via synergistic mechanisms that use signals with distinct functions.


Assuntos
Citrulinação/fisiologia , DNA/metabolismo , Histonas/metabolismo , Inflamação/metabolismo , Neutrófilos/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Cromatina/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Ativação de Neutrófilo/fisiologia
3.
Cell Host Microbe ; 27(2): 277-289.e6, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32053791

RESUMO

Hookworms cause a major neglected tropical disease, occurring after larvae penetrate the host skin. Neutrophils are phagocytes that kill large pathogens by releasing neutrophil extracellular traps (NETs), but whether they target hookworms during skin infection is unknown. Using a murine hookworm, Nippostrongylus brasiliensis, we observed neutrophils being rapidly recruited and deploying NETs around skin-penetrating larvae. Neutrophils depletion or NET inhibition altered larvae behavior and enhanced the number of adult worms following murine infection. Nevertheless, larvae were able to mitigate the effect of NETs by secreting a deoxyribonuclease (Nb-DNase II) to degrade the DNA backbone. Critically, neutrophils were able to kill larvae in vitro, which was enhanced by neutralizing Nb-DNase II. Homologs of Nb-DNase II are present in other nematodes, including the human hookworm, Necator americanus, which also evaded NETs in vitro. These findings highlight the importance of neutrophils in hookworm infection and a potential conserved mechanism of immune evasion.


Assuntos
Ancylostomatoidea/imunologia , Endodesoxirribonucleases/biossíntese , Armadilhas Extracelulares/metabolismo , Evasão da Resposta Imune , Animais , Interações Hospedeiro-Parasita , Camundongos , Neutrófilos/metabolismo , Nippostrongylus/imunologia , Infecções por Strongylida/imunologia
5.
Nat Med ; 23(6): 681-691, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28459437

RESUMO

Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.


Assuntos
Asma/imunologia , Citocinas/imunologia , DNA/imunologia , Armadilhas Extracelulares/imunologia , Infecções por Picornaviridae/imunologia , Hipersensibilidade Respiratória/imunologia , Infecções Respiratórias/imunologia , Células Th2/imunologia , Adulto , Animais , Estudos de Casos e Controles , Dermatophagoides farinae/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Rhinovirus , Adulto Jovem
6.
Immunity ; 46(3): 421-432, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28314592

RESUMO

How the number of immune cells recruited to sites of infection is determined and adjusted to differences in the cellular stoichiometry between host and pathogen is unknown. Here, we have uncovered a role for reactive oxygen species (ROS) as sensors of microbe size. By sensing the differential localization of ROS generated in response to microbes of different size, neutrophils tuned their interleukin (IL)-1ß expression via the selective oxidation of NF-κB, in order to implement distinct inflammatory programs. Small microbes triggered ROS intracellularly, suppressing IL-1ß expression to limit neutrophil recruitment as each phagocyte eliminated numerous pathogens. In contrast, large microbes triggered ROS extracellularly, amplifying IL-1ß expression to recruit numerous neutrophils forming cooperative clusters. Defects in ROS-mediated microbe size sensing resulted in large neutrophil infiltrates and clusters in response to small microbes that contribute to inflammatory disease. These findings highlight the impact of ROS localization on signal transduction.


Assuntos
Infecções Bacterianas/imunologia , Inflamação/microbiologia , Micoses/imunologia , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/imunologia , Animais , Bactérias/imunologia , Bactérias/patogenicidade , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fungos Mitospóricos/imunologia , Fungos Mitospóricos/patogenicidade , Infiltração de Neutrófilos/imunologia
7.
Nat Immunol ; 17(11): 1273-1281, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27595232

RESUMO

Siglec-9 is a sialic-acid-binding lectin expressed predominantly on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers and results in increased sialylation. Thus, when the mucin MUC1 is expressed on cancer cells, it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we found that this cancer-specific MUC1 glycoform, through engagement of Siglec-9, 'educated' myeloid cells to release factors associated with determination of the tumor microenvironment and disease progression. Moreover, MUC1-ST induced macrophages to display a tumor-associated macrophage (TAM)-like phenotype, with increased expression of the checkpoint ligand PD-L1. Binding of MUC1-ST to Siglec-9 did not activate the phosphatases SHP-1 or SHP-2 but, unexpectedly, induced calcium flux that led to activation of the kinases MEK-ERK. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway that follows engagement of Siglec-9.


Assuntos
Antígenos CD/metabolismo , Mucina-1/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Microambiente Tumoral/imunologia , Antígenos CD/genética , Biomarcadores , Diferenciação Celular , Linhagem Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Glicosilação , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células Mieloides/citologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/genética , Neoplasias/patologia , Fenótipo , Ligação Proteica , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética
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