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1.
Eur Respir J ; 61(5)2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36922030

RESUMO

BACKGROUND: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). METHODS: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. RESULTS: Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p<0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p<0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p<0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p<0.001), confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. CONCLUSIONS: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.


Assuntos
COVID-19 , Influenza Humana , Lesão Pulmonar , Humanos , Monócitos/metabolismo , Quimiocinas CXC/metabolismo , Receptores Virais/metabolismo , Receptores CXCR6 , Receptores de Quimiocinas/metabolismo , Síndrome de COVID-19 Pós-Aguda , Ligantes , Convalescença , Receptores Depuradores/metabolismo , Quimiocina CXCL16 , Gravidade do Paciente
2.
Proc Natl Acad Sci U S A ; 115(42): 10738-10743, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30279177

RESUMO

γδ T cells are enriched at barrier sites such as the gut, skin, and lung, where their roles in maintaining barrier integrity are well established. However, how these cells contribute to homeostasis at the gingiva, a key oral barrier and site of the common chronic inflammatory disease periodontitis, has not been explored. Here we demonstrate that the gingiva is policed by γδ T cells with a T cell receptor (TCR) repertoire that diversifies during development. Gingival γδ T cells accumulated rapidly after birth in response to barrier damage, and strikingly, their absence resulted in enhanced pathology in murine models of the oral inflammatory disease periodontitis. Alterations in bacterial communities could not account for the increased disease severity seen in γδ T cell-deficient mice. Instead, gingival γδ T cells produced the wound healing associated cytokine amphiregulin, administration of which rescued the elevated oral pathology of tcrδ-/- mice. Collectively, our results identify γδ T cells as critical constituents of the immuno-surveillance network that safeguard gingival tissue homeostasis.


Assuntos
Anfirregulina/metabolismo , Homeostase , Boca/imunologia , Periodontite/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Subpopulações de Linfócitos T/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Boca/metabolismo , Periodontite/metabolismo , Periodontite/patologia , Subpopulações de Linfócitos T/metabolismo
3.
J Exp Med ; 221(8)2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38819409

RESUMO

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.


Assuntos
Plasticidade Celular , Interleucina-17 , Periodontite , Células Th17 , Células Th17/imunologia , Animais , Periodontite/imunologia , Periodontite/patologia , Plasticidade Celular/imunologia , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Células T Auxiliares Foliculares/imunologia , Gengiva/imunologia , Gengiva/patologia , Imunoglobulina G/imunologia , Perda do Osso Alveolar/imunologia , Perda do Osso Alveolar/patologia
4.
Matrix Biol ; 127: 23-37, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38331051

RESUMO

BACKGROUND: The kidney contains distinct glomerular and tubulointerstitial compartments with diverse cell types and extracellular matrix components. The role of immune cells in glomerular environment is crucial for dampening inflammation and maintaining homeostasis. Macrophages are innate immune cells that are influenced by their tissue microenvironment. However, the multifunctional role of kidney macrophages remains unclear. METHODS: Flow and imaging cytometry were used to determine the relative expression of CD81 and CX3CR1 (C-X3-C motif chemokine receptor 1) in kidney macrophages. Monocyte replenishment was assessed in Cx3cr1CreER X R26-yfp-reporter and shielded chimeric mice. Bulk RNA-sequencing and mass spectrometry-based proteomics were performed on isolated kidney macrophages from wild type and Col4a5-/- (Alport) mice. RNAscope was used to visualize transcripts and macrophage purity in bulk RNA assessed by CIBERSORTx analyses. RESULTS: In wild type mice we identified three distinct kidney macrophage subsets using CD81 and CX3CR1 and these subsets showed dependence on monocyte replenishment. In addition to their immune function, bulk RNA-sequencing of macrophages showed enrichment of biological processes associated with extracellular matrix. Proteomics identified collagen IV and laminins in kidney macrophages from wild type mice whilst other extracellular matrix proteins including cathepsins, ANXA2 and LAMP2 were enriched in Col4a5-/- (Alport) mice. A subset of kidney macrophages co-expressed matrix and macrophage transcripts. CONCLUSIONS: We identified CD81 and CX3CR1 positive kidney macrophage subsets with distinct dependence for monocyte replenishment. Multiomic analysis demonstrated that these cells have diverse functions that underscore the importance of macrophages in kidney health and disease.


Assuntos
Nefropatias , Macrófagos , Camundongos , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Macrófagos/metabolismo , Rim/metabolismo , Inflamação/metabolismo , Nefropatias/metabolismo , RNA/metabolismo
5.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33635312

RESUMO

Hematopoietic stem cells reside in the bone marrow, where they generate the effector cells that drive immune responses. However, in response to inflammation, some hematopoietic stem and progenitor cells (HSPCs) are recruited to tissue sites and undergo extramedullary hematopoiesis. Contrasting with this paradigm, here we show residence and differentiation of HSPCs in healthy gingiva, a key oral barrier in the absence of overt inflammation. We initially defined a population of gingiva monocytes that could be locally maintained; we subsequently identified not only monocyte progenitors but also diverse HSPCs within the gingiva that could give rise to multiple myeloid lineages. Gingiva HSPCs possessed similar differentiation potentials, reconstitution capabilities, and heterogeneity to bone marrow HSPCs. However, gingival HSPCs responded differently to inflammatory insults, responding to oral but not systemic inflammation. Combined, we highlight a novel pathway of myeloid cell development at a healthy barrier, defining a gingiva-specific HSPC network that supports generation of a proportion of the innate immune cells that police this barrier.


Assuntos
Gengiva/citologia , Gengiva/imunologia , Células Progenitoras Mieloides/citologia , Células Progenitoras Mieloides/imunologia , Animais , Medula Óssea/metabolismo , Feminino , Hematopoese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Bucal/citologia , Mucosa Bucal/imunologia , RNA-Seq/métodos , Análise de Célula Única/métodos
6.
Med ; 2(6): 720-735.e4, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33821250

RESUMO

BACKGROUND: Emerging studies indicate that some coronavirus disease 2019 (COVID-19) patients suffer from persistent symptoms, including breathlessness and chronic fatigue; however, the long-term immune response in these patients presently remains ill-defined. METHODS: Here, we describe the phenotypic and functional characteristics of B and T cells in hospitalized COVID-19 patients during acute disease and at 3-6 months of convalescence. FINDINGS: We report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8+ T cells as well as elevated production of type 1 cytokines and interleukin-17 (IL-17). Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to Toll-like receptor activation, skewed toward a pro-inflammatory phenotype. Whereas the frequency of IL-6+ B cells was restored in convalescent patients irrespective of clinical outcome, the recovery of IL-10+ B cells was associated with the resolution of lung pathology. CONCLUSIONS: Our data detail lymphocyte alterations in previously hospitalized COVID-19 patients up to 6 months following hospital discharge and identify 3 subgroups of convalescent patients based on distinct lymphocyte phenotypes, with 1 subgroup associated with poorer clinical outcome. We propose that alterations in B and T cell function following hospitalization with COVID-19 could affect longer-term immunity and contribute to some persistent symptoms observed in convalescent COVID-19 patients. FUNDING: Provided by UKRI, Lister Institute of Preventative Medicine, the Wellcome Trust, The Kennedy Trust for Rheumatology Research, and 3M Global Giving.


Assuntos
COVID-19 , Linfócitos T CD8-Positivos , Citocinas , Humanos , Interleucina-10 , Interleucina-6 , SARS-CoV-2
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