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1.
Sci Adv ; 10(38): eadq1476, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39292787

RESUMO

Cross-talk between hematopoietic stem and progenitor cells (HSPCs) and bone marrow (BM) cells is critical for homing and sustained engraftment after transplantation. In particular, molecular and physical adaptation of sinusoidal endothelial cells (ECs) promote HSPC BM occupancy; however, signals that govern these events are not well understood. Extracellular vesicles (EVs) are mediators of cell-cell communication crucial in shaping tissue microenvironments. Here, we demonstrate that integrin α4ß7 on murine HSPC EVs targets uptake into ECs. In BM ECs, HSPC EVs induce up-regulation of C-C motif chemokine receptor 2 (CCR2) ligands that synergize with CXCL12-CXCR4 signaling to promote BM homing. In nonirradiated murine models, marrow preconditioning with HSPC EVs or recombinant CCR2 ligands improves homing and early graft occupancy after transplantation. These findings identify a role for HSPC EVs in remodeling ECs, newly define CCR2-dependent graft homing, and inform novel translational conditioning strategies to improve HSPC transplantation.


Assuntos
Medula Óssea , Vesículas Extracelulares , Células-Tronco Hematopoéticas , Receptores CCR2 , Animais , Camundongos , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Movimento Celular , Quimiocina CXCL12/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/citologia , Vesículas Extracelulares/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Camundongos Endogâmicos C57BL , Receptores CCR2/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Humanos
2.
WIREs Mech Dis ; : e1646, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38634218

RESUMO

The noncanonical NFκB signaling pathway mediates the biological functions of diverse cell survival, growth, maturation, and differentiation factors that are important for the development and maintenance of hematopoietic cells and immune organs. Its dysregulation is associated with a number of immune pathologies and malignancies. Originally described as the signaling pathway that controls the NFκB family member RelB, we now know that noncanonical signaling also controls NFκB RelA and cRel. Here, we aim to clarify our understanding of the molecular network that mediates noncanonical NFκB signaling and review the human diseases that result from a deficient or hyper-active noncanonical NFκB pathway. It turns out that dysregulation of RelA and cRel, not RelB, is often implicated in mediating the resulting pathology. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Cancer > Molecular and Cellular Physiology Immune System Diseases > Stem Cells and Development.

3.
J Allergy Clin Immunol ; 152(5): 1261-1272, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37460023

RESUMO

BACKGROUND: Autoimmune diseases are leading causes of ill health and morbidity and have diverse etiology. Two signaling pathways are key drivers of autoimmune pathology, interferon and nuclear factor-κB (NF-κB)/RelA, defining the 2 broad labels of interferonopathies and relopathies. Prior work has established that genetic loss of function of the NF-κB subunit RelB leads to autoimmune and inflammatory pathology in mice and humans. OBJECTIVE: We sought to characterize RelB-deficient autoimmunity by unbiased profiling of the responses of immune sentinel cells to stimulus and to determine the functional role of dysregulated gene programs in the RelB-deficient pathology. METHODS: Transcriptomic profiling was performed on fibroblasts and dendritic cells derived from patients with RelB deficiency and knockout mice, and transcriptomic responses and pathology were assessed in mice deficient in both RelB and the type I interferon receptor. RESULTS: We found that loss of RelB in patient-derived fibroblasts and mouse myeloid cells results in elevated induction of hundreds of interferon-stimulated genes. Removing hyperexpression of the interferon-stimulated gene program did not ameliorate the autoimmune pathology of RelB knockout mice. Instead, we found that RelB suppresses a different set of inflammatory response genes in a manner that is independent of interferon signaling but associated with NF-κB binding motifs. CONCLUSION: Although transcriptomic profiling would describe RelB-deficient autoimmune disease as an interferonopathy, the genetic evidence indicates that the pathology in mice is interferon-independent.


Assuntos
Doenças Autoimunes , NF-kappa B , Animais , Humanos , Camundongos , Doenças Autoimunes/genética , Interferons/genética , Camundongos Knockout , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Transcrição RelB/genética
4.
Head Neck Pathol ; 15(4): 1299-1302, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33394369

RESUMO

Lipomas are common benign mesenchymal neoplasms. Although 13% of lipomas are found in the head and neck, only 0.6% have been reported in the larynx. Of all lipomas, the spindle cell variant is the least common. In the present study, we report a case of supraglottic spindle cell lipoma and review the literature of laryngeal spindle cell lipoma. A 35-year-old male presented with dysphagia and dyspnea and was found to have bilateral supraglottic lesions causing airway obstruction. The masses were resected endoscopically. Final pathology demonstrated mature adipocytes and spindle cells, with immunohistochemical patterns supportive of spindle cell lipoma. Spindle cell lipomas have rarely been reported in the upper airway. To our knowledge, this is the youngest patient reported to date. These lipomas are uncommon benign neoplasms and should be distinguished from aggressive mesenchymal neoplasms such as liposarcoma variants to guide appropriate conservative but curative therapy.


Assuntos
Neoplasias Laríngeas/diagnóstico , Lipoma/diagnóstico , Adulto , Biópsia , Meios de Contraste , Diagnóstico Diferencial , Humanos , Achados Incidentais , Masculino , Tomografia Computadorizada por Raios X
5.
J Clin Invest ; 126(11): 4331-4345, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27721238

RESUMO

Scleroderma is a group of skin-fibrosing diseases for which there are no effective treatments. A feature of the skin fibrosis typical of scleroderma is atrophy of the dermal white adipose tissue (DWAT). Adipose tissue contains adipose-derived mesenchymal stromal cells (ADSCs) that have regenerative and reparative functions; however, whether DWAT atrophy in fibrosis is accompanied by ADSC loss is poorly understood, as are the mechanisms that might maintain ADSC survival in fibrotic skin. Here, we have shown that DWAT ADSC numbers were reduced, likely because of cell death, in 2 murine models of scleroderma skin fibrosis. The remaining ADSCs showed a partial dependence on dendritic cells (DCs) for survival. Lymphotoxin ß (LTß) expression in DCs maintained ADSC survival in fibrotic skin by activating an LTß receptor/ß1 integrin (LTßR/ß1 integrin) pathway on ADSCs. Stimulation of LTßR augmented the engraftment of therapeutically injected ADSCs, which was associated with reductions in skin fibrosis and improved skin function. These findings provide insight into the effects of skin fibrosis on DWAT ADSCs, identify a DC-ADSC survival axis in fibrotic skin, and suggest an approach for improving mesenchymal stromal cell therapy in scleroderma and other diseases.


Assuntos
Células Dendríticas/metabolismo , Derme/metabolismo , Esclerodermia Difusa/metabolismo , Gordura Subcutânea/metabolismo , Animais , Sobrevivência Celular/genética , Células Dendríticas/patologia , Derme/patologia , Modelos Animais de Doenças , Feminino , Fibrose , Integrina beta1/genética , Integrina beta1/metabolismo , Linfotoxina-beta/genética , Linfotoxina-beta/metabolismo , Camundongos , Camundongos Knockout , Esclerodermia Difusa/genética , Esclerodermia Difusa/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Gordura Subcutânea/patologia
6.
Trends Immunol ; 37(11): 764-777, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27638128

RESUMO

During normal and pathologic immune responses, lymph nodes can swell considerably. The lymph node vascular-stromal compartment supports and regulates the developing immune responses and undergoes dynamic expansion and remodeling. Recent studies have shown that dendritic cells (DCs), best known for their antigen presentation roles, can directly regulate the vascular-stromal compartment, pointing to a new perspective on DCs as facilitators of lymphoid tissue function. Here, we review the phases of lymph node vascular-stromal growth and remodeling during immune responses, discuss the roles of DCs, and discuss how this understanding can potentially be used for developing novel therapeutic approaches.


Assuntos
Apresentação de Antígeno , Células Dendríticas/imunologia , Imunidade , Imunoterapia/métodos , Linfonodos/imunologia , Células Estromais/fisiologia , Remodelação Vascular/imunologia , Animais , Antígenos/imunologia , Antígenos/metabolismo , Comunicação Celular/imunologia , Humanos , Imunoterapia/tendências , Peptídeos/imunologia , Peptídeos/metabolismo
7.
Curr Opin Rheumatol ; 27(6): 530-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26352734

RESUMO

PURPOSE OF REVIEW: In this review of the literature from 2014 through mid-2015, we examine new data that shed light on how macrophages and other innate immune cells and signals contribute to inflammation, vascular dysfunction, and fibrosis in scleroderma. RECENT FINDINGS: Recent human studies have focused on changes early in scleroderma, and linked macrophages to inflammation in skin and progression of lung disease. Plasmacytoid dendritic cells have been implicated in vascular dysfunction. In mice, several factors have been identified that influence macrophage activation and experimental fibrosis. However, emerging data also suggest that myeloid cells can have differential effects in fibrosis. Sustained signaling through different toll-like receptors can lead to inflammation or fibrosis, and these signals can influence both immune and nonimmune cells. SUMMARY: There are many types of innate immune cells that can potentially contribute to scleroderma and will be worth exploring in detail. Experimentally dissecting the roles of macrophages based on ontogeny and activation state, and the innate signaling pathways in the tissue microenvironment, may also lead to better understanding of scleroderma pathogenesis.


Assuntos
Imunidade Inata , Macrófagos/imunologia , Escleroderma Sistêmico/imunologia , Animais , Células Dendríticas/imunologia , Fibrose/imunologia , Humanos , Inflamação/imunologia , Camundongos
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