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1.
Semin Immunol ; 54: 101516, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-34728120

RESUMEN

Neutrophils are vital for the innate immune system's control of pathogens and neutrophil deficiency can render the host susceptible to life-threatening infections. Neutrophil responses must also be tightly regulated because excessive production, recruitment or activation of neutrophils can cause tissue damage in both acute and chronic inflammatory diseases. Granulocyte colony stimulating factor (G-CSF) is a key regulator of neutrophil biology, from production, differentiation, and release of neutrophil precursors in the bone marrow (BM) to modulating the function of mature neutrophils outside of the BM, particularly at sites of inflammation. G-CSF acts by binding to its cognate cell surface receptor on target cells, causing the activation of intracellular signalling pathways mediating the proliferation, differentiation, function, and survival of cells in the neutrophil lineage. Studies in humans and mice demonstrate that G-CSF contributes to protecting the host against infection, but conversely, it can play a deleterious role in inflammatory diseases. As such, neutrophils and the G-CSF pathway may provide novel therapeutic targets. This review will focus on understanding the role G-CSF plays in the balance between effective neutrophil mediated host defence versus neutrophil-mediated inflammation and tissue damage in various inflammatory and infectious diseases.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos , Neutrófilos , Animales , Médula Ósea/metabolismo , Diferenciación Celular , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Inflamación/metabolismo , Ratones
2.
Neuropathol Appl Neurobiol ; 49(1): e12888, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36734037

RESUMEN

AIMS: Muscle biopsy techniques range from needle muscle biopsy (NMB) and conchotome biopsy to open surgical biopsy. It is unknown whether specific biopsy techniques offer superior diagnostic yield or differ in procedural complication rates. Therefore, we aimed to compare the diagnostic utility of NMB, conchotome and open muscle biopsies in the assessment of neuromuscular disorders. METHODS: A systematic literature review of the EMBASE and Medline (Ovid) databases was performed to identify original, full-length research articles that described the muscle biopsy technique used to diagnose neuromuscular disease in both adult and paediatric patient populations. Studies of any design, excluding case reports, were eligible for inclusion. Data pertaining to biopsy technique, biopsy yield and procedural complications were extracted. RESULTS: Sixty-four studies reporting the yield of a specific muscle biopsy technique and, or procedural complications were identified. Open surgical biopsies provided a larger tissue sample than any type of percutaneous muscle biopsy. Where anaesthetic details were reported, general anaesthesia was required in 60% of studies that reported open surgical biopsies. Percutaneous biopsies were most commonly performed under local anaesthesia and despite the smaller tissue yield, moderate- to large-gauge needle and conchotome muscle biopsies had an equivalent diagnostic utility to that of open surgical muscle biopsy. All types of muscle biopsy procedures were well tolerated with few adverse events and no scarring complications were reported with percutaneous sampling. CONCLUSIONS: When a histological diagnosis of myopathy is required, moderate- to large-gauge NMB and the conchotome technique appear to have an equivalent diagnostic yield to that of an open surgical biopsy.


Asunto(s)
Enfermedades Musculares , Enfermedades Neuromusculares , Adulto , Niño , Humanos , Biopsia/métodos , Enfermedades Neuromusculares/patología , Biopsia con Aguja/métodos , Enfermedades Musculares/patología , Músculos/patología , Estudios Retrospectivos
3.
Clin Transl Med ; 13(1): e1150, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36653319

RESUMEN

BACKGROUND: Low-density neutrophils (LDN) are a distinct subset of neutrophils rarely detected in healthy people but appear in the blood of patients with autoimmune diseases, including systemic lupus erythematosus (SLE), and are mobilised in response to granulocyte colony-stimulating factor (G-CSF). The aim of this study was to identify novel mechanisms responsible for the pathogenic capacity of LDN in SLE. METHODS: Neutrophils were isolated from donors treated with G-CSF, and whole-cell proteomic analysis was performed on LDN and normal-density neutrophils. RESULTS: CD98 is significantly upregulated in LDN from G-CSF donors and defines a subset of LDN within the blood of SLE patients. CD98 is a transmembrane protein that dimerises with L-type amino acid transporters. We show that CD98 is responsible for the increased bioenergetic capacity of LDN. CD98 on LDN mediates the uptake of essential amino acids that are used by mitochondria to produce adenosine triphosphate, especially in the absence of glucose. Inhibition of CD98 reduces the metabolic flexibility of this population, which may limit their pathogenic capacity. CD98+ LDN produce more proinflammatory cytokines and chemokines than their normal density counterparts and are resistant to apoptosis, which may also contribute to tissue inflammation and end organ damage in SLE. CONCLUSIONS: CD98 provides a phenotypic marker for LDN that facilitates identification of this population without density-gradient separation and represents a novel therapeutic target to limit its pathogenic capacity.


Asunto(s)
Proteína-1 Reguladora de Fusión , Lupus Eritematoso Sistémico , Neutrófilos , Humanos , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos/metabolismo , Neutrófilos/metabolismo , Proteómica , Proteína-1 Reguladora de Fusión/metabolismo
4.
Blood Adv ; 5(11): 2550-2562, 2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-34100903

RESUMEN

Neutrophils help to clear pathogens and cellular debris, but can also cause collateral damage within inflamed tissues. Prolonged neutrophil residency within an inflammatory niche can exacerbate tissue pathology. Using both genetic and pharmacological approaches, we show that BCL-XL is required for the persistence of neutrophils within inflammatory sites in mice. We demonstrate that a selective BCL-XL inhibitor (A-1331852) has therapeutic potential by causing apoptosis in inflammatory human neutrophils ex vivo. Moreover, in murine models of acute and chronic inflammatory disease, it reduced inflammatory neutrophil numbers and ameliorated tissue pathology. In contrast, there was minimal effect on circulating neutrophils. Thus, we show a differential survival requirement in activated neutrophils for BCL-XL and reveal a new therapeutic approach to neutrophil-mediated diseases.


Asunto(s)
Neutropenia , Neutrófilos , Animales , Apoptosis , Longevidad , Ratones , Neutropenia/tratamiento farmacológico
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