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1.
Obesity (Silver Spring) ; 31(2): 466-478, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36628649

RESUMO

OBJECTIVE: Colchicine is known to reduce inflammation and improve endothelial cell function and atherosclerosis in obesity, but there is little knowledge of the specific circulating leukocyte populations that are modulated by colchicine. METHODS: A secondary analysis of a double-blind randomized controlled trial of colchicine 0.6 mg or placebo twice daily for 3 months on circulating leukocyte populations and regulation of the immune secretome in 35 adults with obesity was performed. RESULTS: Colchicine altered multiple innate immune cell populations, including dendritic cells and lymphoid progenitor cells, monocytes, and natural killer cells when compared with placebo. Among all subjects and within the colchicine group, changes in natural killer cells were significantly positively associated with reductions in biomarkers of inflammation, including cyclooxygenase 2, pulmonary surfactant-associated protein D, myeloperoxidase, proteinase 3, interleukin-16, and resistin. Changes in dendritic cells were positively correlated with changes in serum heart-type fatty acid-binding protein concentrations. Additionally, colchicine treatment reduced cluster of differentiation (CD) CD4+ T effector cells and CD8+ T cytotoxic cells. Conversely, colchicine increased CD4+ and CD8+ T central memory cells and activated CD38High CD8+ T cells. Changes in CD4+ T effector cells were associated with changes in serum heart-type fatty acid-binding protein. CONCLUSIONS: In adults with obesity, colchicine significantly affects circulating leukocyte populations involved in both innate and adaptive immune systems along with the associated inflammatory secretome.


Assuntos
Colchicina , Leucócitos Mononucleares , Adulto , Humanos , Colchicina/farmacologia , Colchicina/uso terapêutico , Obesidade/complicações , Inflamação/metabolismo , Proteínas de Ligação a Ácido Graxo/uso terapêutico
2.
Sci Rep ; 11(1): 946, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441583

RESUMO

Macrophages and monocytes are important for clearance of Leishmania infections. However, immune evasion tactics employed by the parasite results in suppressed inflammatory responses, marked by deficient macrophage functions and increased accumulation of monocytes. This results in an ineffective ability to clear parasite loads. Allograft Inflammatory Factor-1 (AIF1) is expressed in myeloid cells and serves to promote immune responses. However, AIF1 involvement in monocyte and macrophage functions during parasitic infections has not been explored. This study now shows that Leishmania donovani inhibits AIF1 expression in macrophages to block pro-inflammatory responses. Mice challenged with the parasite had markedly reduced AIF1 expression in splenic macrophages. Follow-up studies using in vitro approaches confirmed that L. donovani infection in macrophages suppresses AIF1 expression, which correlated with reduction in pro-inflammatory cytokine production and increased parasite load. Ectopic overexpression of AIF1 in macrophages provided protection from infection, marked by robust pro-inflammatory cytokine production and efficient pathogen clearance. Further investigations found that inhibiting AIF1 expression in bone marrow cells or monocytes impaired differentiation into functional macrophages. Collectively, results show that AIF1 is a critical regulatory component governing monocyte and macrophage immune functions and that L. donovani infection can suppress the gene as an immune evasion tactic.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Inflamação/imunologia , Leishmania donovani/metabolismo , Proteínas dos Microfilamentos/metabolismo , Animais , Apoptose , Células da Medula Óssea/citologia , Proteínas de Ligação ao Cálcio/fisiologia , Diferenciação Celular , Feminino , Evasão da Resposta Imune/imunologia , Evasão da Resposta Imune/fisiologia , Inflamação/metabolismo , Leishmania donovani/patogenicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/fisiologia , Monócitos/imunologia , Monócitos/metabolismo
3.
JCI Insight ; 5(10)2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32434993

RESUMO

Allograft inflammatory factor-1 (AIF1) is a calcium-responsive cytoplasmic scaffold protein that directs hematopoiesis and immune responses within dendritic cells (DC) and macrophages. Although the role of AIF1 in transplant rejection and rheumatoid arthritis has been explored, little is known about its role in type 1 diabetes. Here, we show that in vivo silencing of AIF1 in NOD mice restrained infiltration of immune cells into the pancreas and inhibited diabetes incidence. Analyses of FACS-sorted CD45neg nonleukocyte populations from resected pancreatic islets showed markedly higher expression of insulin in the AIF1-silenced groups. Evaluation of CD45+ leukocytes revealed diminished infiltration of effector T cells and DC in the absence of AIF1. Transcriptional profiling further revealed a marked decrease in cDC1 DC-associated genes CD103, BATF3, and IRF8, which are required for orchestrating polarized type 1 immunity. Reduced T cell numbers within the islets were observed, with concomitant lower levels of IFN-γ and T-bet in AIF1-silenced cohorts. In turn, there was a reciprocal increase in functionally suppressive pancreas-resident CD25+Foxp3+CD4+ Tregs. Taken together, results show that AIF1 expression in myeloid cells plays a pivotal role in promoting type 1 diabetes and that its suppression restrains insulitis by shifting the immune microenvironment toward tolerance.


Assuntos
Proteínas de Ligação ao Cálcio/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Proteínas dos Microfilamentos/imunologia , Células Mieloides/imunologia , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Mieloides/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
4.
Sci Rep ; 10(1): 4362, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152396

RESUMO

Therapeutic approaches to combat type 1 diabetes (T1D) include donor pancreas transplantation, exogenous insulin administration and immunosuppressive therapies. However, these clinical applications are limited due to insufficient tissue compatible donors, side effects of exogenous insulin administration and/or increased onset of opportunistic infections attributable to induced global immunosuppression. An alternative approach to alleviate disease states is to utilize insulin-producing pancreatic islets seeded in a bioscaffold for implantation into diabetic recipients. The present studies now report that a newly developed cationic polymer biomaterial serves as an efficient bioscaffold for delivery of donor syngeneic pancreatic islet cells to reverse hyperglycemia in murine streptozotocin induced- or non-obese diabetic mouse models of T1D. Intraperitoneal implantation of pancreatic islets seeded within the copolymer bioscaffold supports long-term cell viability, response to extracellular signaling cues and ability to produce soluble factors into the microenvironment. Elevated insulin levels were measured in recipient diabetic mice upon implantation of the islet-seeded biomaterial coupled with reduced blood glucose levels, collectively resulting in increased survival and stabilization of metabolic indices. Importantly, the implanted islet-seeded biomaterial assembled into a solid organoid substructure that reorganized the extracellular matrix compartment and recruited endothelial progenitors for neovascularization. This allowed survival of the graft long-term in vivo and access to the blood for monitoring glucose levels. These results highlight the novelty, simplicity and effectiveness of this biomaterial for tissue regeneration and in vivo restoration of organ functions.


Assuntos
Hiperglicemia/sangue , Insulina/biossíntese , Ilhotas Pancreáticas/metabolismo , Organoides , Técnicas de Cultura de Tecidos , Alicerces Teciduais , Animais , Glicemia , Sobrevivência Celular , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Sobrevivência de Enxerto , Hiperglicemia/terapia , Transplante das Ilhotas Pancreáticas , Camundongos
5.
Front Immunol ; 10: 173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800127

RESUMO

The multistep differentiation process from hematopoietic stem cells through common myeloid progenitors into committed dendritic cell (DC) subsets remains to be fully addressed. These studies now show that Allograft Inflammatory Factor-1 (AIF1) is required for differentiation of classical DC type 1 (cDC1) subsets and monocyte-derived DC (Mo-DC). Phenotypic studies found that AIF1 expression increased in committed subsets differentiating from common myeloid progenitors (CMP). However, silencing AIF1 expression in hematopoietic stem progenitors restrained the capacity to differentiate into Mo-DC and cDC1 cell subsets under GM-CSF or Flt3-L stimuli conditions, respectively. This was further marked by restrained expression of IRF8, which is critical for development of Mo-DC and cDC1 subsets. As a result, absence of AIF1 restrained the cells at the Lin-CD117+FcγR-CD34+ CMP stage. Further biochemical studies revealed that abrogating AIF1 resulted in inhibition of the NFκB family member RelB expression and p38 MAPK phosphorylation during differentiation of Mo-DC. Lastly, protein binding studies identified that AIF1 interacts with protein kinase C (PKC) to influence downstream signaling pathways. Taken together, this is the first report showing a novel role of AIF1 as a calcium-responsive scaffold protein that supports IRF8 expression and interacts with PKC to drive NFκB-related RelB for successfully differentiating hematopoietic progenitor cells into cDC and Mo-DC subsets under Flt3-L and GM-CSF stimuli, respectively.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular/fisiologia , Células Dendríticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas dos Microfilamentos/metabolismo , Monócitos/citologia , Fator de Transcrição RelB/metabolismo , Animais , Células da Medula Óssea/citologia , Proteínas de Ligação ao Cálcio/genética , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Técnicas de Silenciamento de Genes , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hematopoese/efeitos dos fármacos , Masculino , Proteínas de Membrana/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/genética , Subunidade p50 de NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , RNA Interferente Pequeno/genética , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Immunology ; 156(2): 136-146, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30317558

RESUMO

Phagocytosis, macropinocytosis and antigen presentation by dendritic cells (DC) requires reorganization of the actin cytoskeleton. Drebrin (Dbn1) is an actin binding and stabilizing protein with roles in endocytosis, formation of dendrite spines in neurons and coordinating cell-cell synapses in immune cells. However, its role in DC phagocytosis and antigen presentation is unknown. These studies now report that silencing of Dbn1 in DC resulted in restrained cell surface display of receptors, most notably MHC class I and II and co-stimulatory molecules. This, as expected, resulted in impaired antigen-specific T-cell activation and proliferation. Studies additionally revealed that knockdown of Dbn1 in DC impaired macropinocytosis and phagocytosis. However, there was a concomitant increase in fluid-phase uptake, suggesting that Dbn1 is responsible for the differential control of macropinocytosis versus micropinocytosis activities. Taken together, these findings now reveal that Dbn1 plays a major role in coordinating the actin cytoskeletal activities responsible for antigen presentation in DC.


Assuntos
Apresentação de Antígeno , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Neuropeptídeos/imunologia , Fagocitose , Animais , Citoesqueleto/genética , Citoesqueleto/imunologia , Células Dendríticas/citologia , Técnicas de Inativação de Genes , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Sinapses Imunológicas/genética , Sinapses Imunológicas/imunologia , Ativação Linfocitária/genética , Camundongos , Camundongos Transgênicos , Neuropeptídeos/genética , Linfócitos T/citologia , Linfócitos T/imunologia
7.
J Leukoc Biol ; 105(1): 123-130, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30512224

RESUMO

Allograft Inflammatory Factor-1 (AIF1) is a cytoplasmic scaffold protein that contains Ca2+ binding EF-hand and PDZ interaction domains important for mediating intracellular signaling complexes in immune cells. The protein plays a dominant role in both macrophage- and dendritic cell (DC)-mediated inflammatory responses. This study now reports that AIF1 expression in DC is important in directing CD8+ T cell effector responses. Silencing AIF1 expression in murine CD11c+ DC suppressed antigen-specific CD8+ T cell activation, marked by reduced CXCR3, IFNγ and Granzyme B expression, and restrained proliferation. These primed CD8+ T cells had impaired cytotoxic killing of target cells in vitro. In turn, studies identified that AIF1 silencing in DC robustly expanded IL-10 producing CD8+ CD122+ PD-1+ regulatory T cells that suppressed neighboring immune effector responses through both IL-10 and PD-1-dependent mechanisms. In vivo studies recapitulated bystander suppression of antigen-responsive CD4+ T cells by the CD8+ Tregs expanded from the AIF1 silenced DC. These studies further demonstrate that AIF1 expression in DC serves as a potent governor of cognate T cell responses and present a novel target for engineering tolerogenic DC-based immunotherapies.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Dendríticas/metabolismo , Inativação Gênica , Interleucina-10/metabolismo , Proteínas dos Microfilamentos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/metabolismo , Transferência Adotiva , Animais , Proliferação de Células , Subunidade beta de Receptor de Interleucina-2/metabolismo , Subpopulações de Linfócitos/metabolismo , Camundongos Endogâmicos C57BL
8.
Front Immunol ; 8: 1502, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29167673

RESUMO

Allograft inflammatory factor-1 (AIF1) is a cytoplasmic scaffold protein shown to influence immune responses in macrophages and microglial cells. The protein contains Ca2+ binding EF-hand and PDZ interaction domains important for mediating intracellular signaling complexes. This study now reports that AIF1 is expressed in CD11c+ dendritic cells (DC) and silencing of expression restrains induction of antigen-specific CD4+ T cell effector responses. AIF1 knockdown in murine DC resulted in impaired T cell proliferation and skewed polarization away from T helper type 1 and 17 fates. In turn, there was a parallel expansion of IL-10-producing and CD25+Foxp3+ T regulatory subsets. These studies are the first to demonstrate that AIF1 expression in DC serves as a potent governor of cognate T cell responses and presents a novel target for engineering tolerogenic DC-based immunotherapies.

10.
Int Immunol ; 29(3): 121-131, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28369442

RESUMO

Fascin is an actin-bundling protein that, among immune cells, is restricted to expression in dendritic cells (DCs). Previous reports have suggested that fascin plays an important role in governing DC antigen presentation to CD4+ T cells. However, no report has clearly linked the receptor-ligand engagement that can direct downstream regulation of fascin expression. In this study, bone marrow-derived DCs from wild-type versus CD40-knockout C57BL/6 mice were used to elucidate the mechanisms of fascin expression and activity upon CD40-CD40 ligand (CD40L) engagement. These investigations now show that CD40 engagement governs fascin expression in DCs to promote CD4+ T-cell cytokine production. Absence of CD40 signaling resulted in diminished fascin expression in DCs and was associated with impaired CD4+ T-cell responses. Furthermore, the study found that loss of CD40-CD40L engagement resulted in reduced DC-T-cell contacts. Rescue by ectopic fascin expression in CD40-deficient DCs was able to re-establish sustained contacts with T cells and restore cytokine production. Taken together, these results show that cross-talk through CD40-CD40L signaling drives elevated fascin expression in DCs to support acquisition of full T-cell responses.


Assuntos
Apresentação de Antígeno , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Ligante de CD40/imunologia , Proteínas de Transporte/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Proteínas dos Microfilamentos/biossíntese , Animais , Antígenos CD40/deficiência , Proteínas de Transporte/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/imunologia
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