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1.
Biomaterials ; 312: 122731, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39153324

RESUMO

Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-ß (CSF1R/CCR2/TGF-ß Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment.


Assuntos
Monócitos , Receptor de Fator Estimulador de Colônias de Macrófagos , Receptores CCR2 , Microambiente Tumoral , Humanos , Receptores CCR2/metabolismo , Receptores CCR2/antagonistas & inibidores , Monócitos/metabolismo , Monócitos/imunologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Camundongos , Movimento Celular/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/patologia
2.
Nature ; 633(8028): 155-164, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39232147

RESUMO

Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID1, similar to observations in other infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6-8. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals.


Assuntos
Testosterona , Pessoas Transgênero , Adulto , Feminino , Humanos , Masculino , Conjuntos de Dados como Assunto , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-15/imunologia , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Monócitos/imunologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Caracteres Sexuais , Testosterona/efeitos adversos , Testosterona/imunologia , Testosterona/farmacologia , Testosterona/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
3.
Exp Lung Res ; 50(1): 146-159, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39243130

RESUMO

PURPOSE OF THE STUDY: To observe the dynamic changes in monocyte subsets during septic lung injury and to assess the anti-inflammatory role of the sulfotransferase homolog 2 (ST2) receptor. MATERIALS AND METHODS: Dynamic changes of monocyte subsets from patients with septic lung injury and mice post-cecal ligation and puncture (CLP) were monitored. ST2 receptors on mice monocytes and concentrations of IL-33, IL-1ß, IL-12, and IL-27 from peripheral blood or culture supernatant were detected. RESULTS: CD14lowCD16- (Mo0) and CD14++CD16+ (Mo2) monocyte subsets were significantly expanded in patients with sepsis-related acute respiratory distress syndrome. In sepsis model mice, monocyte counts, particularly of Ly6Cint and CDLy6Cint+hi monocytes, were significantly increased. The mean optical density value of TNF-α after CLP mainly increased after 24 h, whereas that of IL-6 was significantly increased at all time points assessed after CLP. The levels of IL-1ß, IL-12, IL-27, and IL-33 increased to variable degrees at 6, 12, 24, and 48h after CLP, and ST2+ monocytes were significantly expanded in sepsis model mice compared to sham-operated mice. ST2 receptor blockade suppressed IL-1ß and IL-12 production in cell culture. CONCLUSIONS: Changes in monocyte subsets expressing the ST2 receptor play an important role in septic lung injury by modulating inflammatory cytokine secretion.


Assuntos
Citocinas , Monócitos , Sepse , Animais , Monócitos/metabolismo , Camundongos , Sepse/metabolismo , Masculino , Humanos , Citocinas/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Interleucina-33/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar Aguda/metabolismo , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Idoso , Interleucina-27/metabolismo
4.
Theranostics ; 14(12): 4713-4729, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39239520

RESUMO

Background: Mesenchymal stem/stromal cells (MSCs) maintain tissue homeostasis in response to microenvironmental perturbations. Toll-like receptors (TLRs) are key sensors for exogenous and endogenous signals produced during injury. In this study, we aimed to investigate whether TLRs affect the homeostatic functions of MSCs after injury. Methods: We examined the expression of TLR2, TLR3 and TLR4 in MSCs, and analyzed the functional significance of TLR2 activation using single-cell RNA sequencing. Additionally, we investigated the effects and mechanisms of TLR2 and its downstream activation in MSCs on the MSCs themselves, on monocytes/macrophages, and in a mouse model of sterile injury-induced inflammatory corneal angiogenesis. Results: MSCs expressed TLR2, which was upregulated by monocytes/macrophages. Activation of TLR2 in MSCs promoted their immunoregulatory and angiostatic functions in monocytes/macrophages and in mice with inflammatory corneal angiogenesis, whereas TLR2 inhibition attenuated these functions. Single-cell RNA sequencing revealed AKR1C1, a gene encoding aldo-keto reductase family 1 member C1, as the most significantly inducible gene in MSCs upon TLR2 stimulation, though its stimulation did not affect cell compositions. AKR1C1 protected MSCs against ferroptosis, increased secretion of anti-inflammatory cytokines, and enhanced their ability to drive monocytes/macrophages towards immunoregulatory phenotypes, leading to the amelioration of inflammatory corneal neovascularization in mice. Conclusion: Our findings suggest that activation of TLR2-AKR1C1 signaling in MSCs serves as an important pathway for the survival and homeostatic activities of MSCs during injury.


Assuntos
Macrófagos , Células-Tronco Mesenquimais , Receptor 2 Toll-Like , Animais , Células-Tronco Mesenquimais/metabolismo , Camundongos , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Humanos , Neovascularização da Córnea/metabolismo , Neovascularização da Córnea/patologia , Neovascularização da Córnea/genética , Monócitos/metabolismo , Masculino , Receptor 4 Toll-Like/metabolismo , Modelos Animais de Doenças , Transdução de Sinais
5.
Sci Adv ; 10(36): eadl6162, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39241063

RESUMO

Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6Chi monocytes and cytokine induction. Depletion of Ly6Chi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6Chi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene-related peptide suppressed the induction of reactive oxygen species in Ly6Chi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Carbapenêmicos , Infecções por Klebsiella , Klebsiella pneumoniae , Pulmão , Nociceptores , Sepse , Animais , Klebsiella pneumoniae/fisiologia , Camundongos , Infecções por Klebsiella/microbiologia , Sepse/metabolismo , Sepse/microbiologia , Pulmão/microbiologia , Pulmão/metabolismo , Carbapenêmicos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Nociceptores/metabolismo , Monócitos/metabolismo , Células Receptoras Sensoriais/metabolismo , Neutrófilos/metabolismo , Modelos Animais de Doenças , Antígenos Ly/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/patologia , Camundongos Endogâmicos C57BL
6.
Cancer Immunol Immunother ; 73(11): 212, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39235612

RESUMO

Patients with lung cancer have a high incidence of tumor recurrence even after curative surgical resection. Some reports indicated that immunosuppressive cells induced by surgical stress could contribute to tumor recurrence after surgery; however, the underlying mechanisms are not fully understood. In this study, we found that increased postoperative blood monocytes served as a risk factor for tumor recurrence in 192 patients with non-small cell lung cancer (NSCLC). We established the lung cancer recurrent mouse model after tumor resection and showed that the surgical stress immediately increased the level of serum monocyte chemoattractant protein-1 (MCP-1), which subsequently increased blood monocytes. These blood monocytes were rapidly recruited into distant micrometastases and became tumor growth-promoting tumor associated macrophages (TAMs). Furthermore, even after the blood MCP-1 and monocytes decreased enough 72 h after tumor resection, TAMs in micrometastases remained rich because the MCP-1 secreted by micrometastases themselves continued to recruit monocytes around the tumor. Consequently, tumor resection triggered the outgrowth of distant metastases via the MCP-1-Monocyte-TAM axis. When we administered the MCP-1 inhibitor to the lung cancer recurrent model mice, blood monocytes decreased after tumor resection, and TAMs in micrometastases also dramatically decreased. Finally, peri- and postoperative treatment with the MCP-1 inhibitor suppressed distant metastases after surgery. Targeting the MCP-1-Monocyte-TAM axis may inhibit surgical stress-induced NSCLC recurrence by attenuating postoperative immunosuppressive monocytes in micrometastases.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiocina CCL2 , Neoplasias Pulmonares , Monócitos , Recidiva Local de Neoplasia , Animais , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Monócitos/imunologia , Monócitos/metabolismo , Camundongos , Humanos , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Masculino , Feminino , Quimiocina CCL2/metabolismo , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Pessoa de Meia-Idade , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Idoso
7.
Front Immunol ; 15: 1454857, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39263222

RESUMO

An oral Controlled Human Infection Model (CHIM) with wild-type S. Typhi was re-established allowing us to explore the development of immunity. In this model, ~55% of volunteers who received the challenge reached typhoid diagnosis criteria (TD), while ~45% did not (NoTD). Intestinal macrophages are one of the first lines of defense against enteric pathogens. Most organs have self-renewing macrophages derived from tissue-resident progenitor cells seeded during the embryonic stage; however, the gut lacks these progenitors, and all intestinal macrophages are derived from circulating monocytes. After infecting gut-associated lymphoid tissues underlying microfold (M) cells, S. Typhi causes a primary bacteremia seeding organs of the reticuloendothelial system. Following days of incubation, a second bacteremia and clinical disease ensue. S. Typhi likely interacts with circulating monocytes or their progenitors in the bone marrow. We assessed changes in circulating monocytes after CHIM. The timepoints studied included 0 hours (pre-challenge) and days 1, 2, 4, 7, 9, 14, 21 and 28 after challenge. TD participants provided extra samples at the time of typhoid diagnosis, and 48-96 hours later (referred as ToD). We report changes in Classical Monocytes -CM-, Intermediate Monocytes -IM- and Non-classical Monocytes -NCM-. Changes in monocyte activation markers were identified only in TD participants and during ToD. CM and IM upregulated molecules related to interaction with bacterial antigens (TLR4, TLR5, CD36 and CD206). Of importance, CM and IM showed enhanced binding of S. Typhi. Upregulation of inflammatory molecules like TNF-α were detected, but mechanisms involved in limiting inflammation were also activated (CD163 and CD354 downregulation). CM upregulated molecules to interact/modulate cells of the adaptive immunity, including T cells (HLA-DR, CD274 and CD86) and B cells (CD257). Both CM and IM showed potential to migrate to the gut as integrin α4ß7 was upregulated. Unsupervised analysis revealed 7 dynamic cell clusters. Five of these belonged to CM showing that this is the main population activated during ToD. Overall, we provide new insights into the changes that diverse circulating monocyte subsets undergo after typhoid diagnosis, which might be important to control this disease since these cells will ultimately become intestinal macrophages once they reach the gut.


Assuntos
Monócitos , Salmonella typhi , Febre Tifoide , Humanos , Febre Tifoide/diagnóstico , Febre Tifoide/imunologia , Salmonella typhi/imunologia , Monócitos/imunologia , Masculino , Adulto , Feminino , Adulto Jovem , Macrófagos/imunologia
8.
Commun Biol ; 7(1): 1131, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271940

RESUMO

Monocytes, the circulating macrophage precursors, contribute to diseases like atherosclerosis and asthma. Long non-coding RNAs (lncRNAs) have been shown to modulate the phenotype and inflammatory capacity of monocytes. We previously discovered the lncRNA SMANTIS, which contributes to cellular phenotype expression by controlling BRG1 in mesenchymal cells. Here, we report that SMANTIS is particularly highly expressed in monocytes and lost during differentiation into macrophages. Moreover, different types of myeloid leukemia presented specific SMANTIS expression patterns. Interaction studies revealed that SMANTIS binds RUNX1, a transcription factor frequently mutated in AML, primarily through its Alu-element on the RUNT domain. RNA-seq after CRISPR/Cas9-mediated deletion of SMANTIS or RUNX1 revealed an association with cell adhesion and both limited the monocyte adhesion to endothelial cells. Mechanistically, SMANTIS KO reduced RUNX1 genomic binding and altered the interaction of RUNX1 with EP300 and CBFB. Collectively, SMANTIS interacts with RUNX1 and attenuates monocyte adhesion, which might limit monocyte vascular egress.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Monócitos , RNA Longo não Codificante , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Humanos , Monócitos/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Adesão Celular/genética , Diferenciação Celular
9.
Sci Immunol ; 9(99): eadp0344, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39241057

RESUMO

Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.


Assuntos
Diferenciação Celular , Células de Langerhans , Monócitos , Pele , Células de Langerhans/imunologia , Células de Langerhans/citologia , Animais , Monócitos/imunologia , Monócitos/citologia , Diferenciação Celular/imunologia , Humanos , Pele/imunologia , Pele/citologia , Camundongos , Camundongos Endogâmicos C57BL , Feminino
10.
Front Immunol ; 15: 1406804, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39229274

RESUMO

Introduction: Immunogenicity refers to the ability of a substance, such as a therapeutic drug, to elicit an immune response. While beneficial in vaccine development, undesirable immunogenicity can compromise the safety and efficacy of therapeutic proteins by inducing anti-drug antibodies (ADAs). These ADAs can reduce drug bioavailability and alter pharmacokinetics, necessitating comprehensive immunogenicity risk assessments starting at early stages of drug development. Given the complexity of immunogenicity, an integrated approach is essential, as no single assay can universally recapitulate the immune response leading to the formation of anti-drug antibodies. Methods: To better understand the Dendritic Cell (DC) contribution to immunogenicity, we developed two flow cytometry-based assays: the DC internalization assay and the DC activation assay. Monocyte-derived dendritic cells (moDCs) were generated from peripheral blood mononuclear cells (PBMCs) and differentiated over a five-day period. The internalization assay measured the accumulation rate of therapeutic antibodies within moDCs, while the activation assay assessed the expression of DC activation markers such as CD40, CD80, CD86, CD83, and DC-SIGN (CD209). To characterize these two assays further, we used a set of marketed therapeutic antibodies. Results: The study highlights that moDCs differentiated for 5 days from freshly isolated monocytes were more prone to respond to external stimuli. The internalization assay has been shown to be highly sensitive to the molecule tested, allowing the use of only 4 donors to detect small but significant differences. We also demonstrated that therapeutic antibodies were efficiently taken up by moDCs, with a strong correlation with their peptide presentation on MHC-II. On the other hand, by monitoring DC activation through a limited set of activation markers including CD40, CD83, and DC-SIGN, the DC activation assay has the potential to compare a series of compounds. These two assays provide a more comprehensive understanding of DC function in the context of immunogenicity, highlighting the importance of both internalization and activation processes in ADA development. Discussion: The DC internalization and activation assays described here address key gaps in existing immunogenicity assessment methods by providing specific and reliable measures of DC function. The assays enhance our ability to pre-clinically evaluate the immunogenic potential of biotherapeutics, thereby improving their safety and efficacy. Future work should focus on further validating these assays and integrating them into a holistic immunogenicity risk assessment framework.


Assuntos
Células Dendríticas , Células Dendríticas/imunologia , Humanos , Citometria de Fluxo , Medição de Risco , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Células Cultivadas , Diferenciação Celular/imunologia , Monócitos/imunologia
11.
Int J Biol Sci ; 20(11): 4114-4127, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39247831

RESUMO

Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In osteosarcoma samples from the Genomic Data Commons data portal, we detected higher levels of NGF and M2 macrophage markers, but not M1 macrophage markers. In cellular experiments, NGF-stimulated osteosarcoma conditional medium was shown to facilitate macrophage polarization from the M0 to the M2 phenotype. NGF also enhanced VCAM-1-dependent monocyte adhesion within the osteosarcoma microenvironment by down-regulating miR-513c-5p levels through the FAK and c-Src cascades. In in vivo xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.


Assuntos
Monócitos , Fator de Crescimento Neural , Osteossarcoma , Microambiente Tumoral , Molécula 1 de Adesão de Célula Vascular , Osteossarcoma/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Humanos , Fator de Crescimento Neural/metabolismo , Animais , Microambiente Tumoral/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo , Camundongos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Macrófagos/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Camundongos Nus
12.
Int J Mol Sci ; 25(17)2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39273424

RESUMO

Communication between natural killer cells (NK cells) and monocytes/macrophages may play an important role in immunomodulation and regulation of inflammatory processes. The aim of this research was to investigate the impact of NK cell-derived large extracellular vesicles on monocyte function because this field is understudied. We studied how NK-cell derived large extracellular vesicles impact on THP-1 cells characteristics after coculturing: phenotype, functions were observed with flow cytometry. In this study, we demonstrated the ability of large extracellular vesicles produced by NK cells to integrate into the membranes of THP-1 cells and influence the viability, phenotype, and functional characteristics of the cells. The results obtained demonstrate the ability of large extracellular vesicles to act as an additional component in the immunomodulatory activity of NK cells in relation to monocytes.


Assuntos
Vesículas Extracelulares , Células Matadoras Naturais , Monócitos , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/citologia , Células THP-1 , Técnicas de Cocultura , Comunicação Celular/imunologia , Sobrevivência Celular , Macrófagos/imunologia , Macrófagos/metabolismo
13.
Int J Mol Sci ; 25(17)2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39273504

RESUMO

In recent years, Raman spectroscopy has garnered growing interest in the field of biomedical research. It offers a non-invasive and label-free approach to defining the molecular fingerprint of immune cells. We utilized Raman spectroscopy on optically trapped immune cells to investigate their molecular compositions. While numerous immune cell types have been studied in the past, the characterization of living human CD3/CD28-stimulated T cell subsets remains incomplete. In this study, we demonstrate the capability of Raman spectroscopy to readily distinguish between naïve and stimulated CD4 and CD8 cells. Additionally, we compared these cells with monocytes and discovered remarkable similarities between stimulated T cells and monocytes. This paper contributes to expanding our knowledge of Raman spectroscopy of immune cells and serves as a launching point for future clinical applications.


Assuntos
Monócitos , Análise Espectral Raman , Subpopulações de Linfócitos T , Humanos , Análise Espectral Raman/métodos , Monócitos/citologia , Monócitos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Pinças Ópticas , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Ativação Linfocitária , Antígenos CD28/metabolismo , Antígenos CD28/imunologia
14.
Int J Mol Sci ; 25(17)2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39273692

RESUMO

Understanding the pig immune function is crucial for disease-resistant breeding and potentially for human health research due to shared immune system features. Immune cell ratios, like monocyte/lymphocyte ratio (MLR) and neutrophil/lymphocyte ratio (NLR), offer a more comprehensive view of immune status compared to individual cell counts. However, research on pig immune cell ratios remains limited. This study investigated MLR and NLR in a Duroc × Erhualian F2 resource population. Heritability analysis revealed high values (0.649 and 0.688 for MLR and NLR, respectively), suggesting a strong genetic component. Furthermore, we employed an ensemble-like GWAS (E-GWAS) strategy and functional annotation analysis to identify 11 MLR-associated and 6 NLR-associated candidate genes. These genes were significantly enriched in immune-related biological processes. These findings provide novel genetic markers and candidate genes associated with porcine immunity, thereby providing valuable insights for addressing biosecurity and animal welfare concerns in the pig industry.


Assuntos
Linfócitos , Monócitos , Neutrófilos , Polimorfismo de Nucleotídeo Único , Animais , Monócitos/metabolismo , Linfócitos/metabolismo , Linfócitos/imunologia , Neutrófilos/metabolismo , Neutrófilos/imunologia , Suínos , Estudo de Associação Genômica Ampla , Masculino , Feminino , Contagem de Leucócitos
15.
Biomater Adv ; 165: 214024, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39232353

RESUMO

Graphene oxide (GO), a carbon-based nanomaterial, presents significant potential across biomedical fields such as bioimaging, drug delivery, biosensors, and phototherapy. This study examines the effects of integrating GO into poly(lactic-co-glycolic acid) (PLGA) scaffolds on human immune cell function. Our results demonstrate that high concentrations of GO reduce the viability of peripheral blood mononuclear cells (PBMCs) following stimulation with anti-CD3 antibody. This reduction extends to T lymphocyte activation, evident from the diminished proliferative response to T cell receptor engagement and impaired differentiation into T helper subsets and regulatory T cells. Interestingly, although GO induces a minimal response in resting monocytes, but it significantly affects both the viability and the differentiation potential of monocytes induced to mature toward M1 pro-inflammatory and M2-like immunoregulatory macrophages. This study seeks to address a critical gap by investigating the in vitro immunomodulatory effects of PLGA scaffolds incorporating various concentrations of GO on primary immune cells, specifically PBMCs isolated from healthy donors. Our findings emphasize the need to optimize the GO to PLGA ratios and scaffold design to advance PLGA-GO-based biomedical applications. STATEMENT OF SIGNIFICANCE: Graphene oxide (GO) holds immense promise for biomedical applications due to its unique properties. However, concerns regarding its potential to trigger adverse immune responses remain. This study addresses this critical gap by investigating the in vitro immunomodulatory effects of PLGA scaffolds incorporating increasing GO concentrations on human peripheral blood mononuclear cells (PBMCs). By elucidating the impact on cell viability, T cell proliferation and differentiation, and the maturation/polarization of antigen-presenting cells, this work offers valuable insights for designing safe and immunologically compatible GO-based biomaterials for future clinical translation.


Assuntos
Grafite , Leucócitos Mononucleares , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Alicerces Teciduais , Grafite/química , Grafite/farmacologia , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Alicerces Teciduais/química , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/química , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia
16.
Nat Commun ; 15(1): 7662, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266531

RESUMO

Most patients with advanced cancer develop cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting. Despite its catastrophic impact on survival, the critical mediators responsible for cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in the advanced cancer milieu and promotes skeletal muscle loss. Unbiased transcriptome analysis reveals that interleukin 36 gamma (IL36G)-producing CD38+ CiMs are induced in chronic monocytic blood cancer characterized by prominent cachexia. Notably, the emergence of CiMs and the activation of CiM-related gene signatures in monocytes are confirmed in various advanced solid cancers. Stimuli of toll-like receptor 4 signaling are responsible for the induction of CiMs. Genetic inhibition of IL36G-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models. These findings indicate that the IL36G-producing subset of neutrophil-like monocytes could be a potential therapeutic target in cancer cachexia.


Assuntos
Caquexia , Monócitos , Músculo Esquelético , Neoplasias , Neutrófilos , Caquexia/metabolismo , Caquexia/etiologia , Monócitos/metabolismo , Monócitos/imunologia , Humanos , Neoplasias/complicações , Neoplasias/metabolismo , Neoplasias/imunologia , Neutrófilos/metabolismo , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Camundongos , Masculino , Transdução de Sinais , Linhagem Celular Tumoral , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Camundongos Endogâmicos C57BL , Interleucinas/metabolismo , Interleucinas/genética , Feminino , Perfilação da Expressão Gênica
17.
Nat Commun ; 15(1): 7998, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266542

RESUMO

Impaired clearance of amyloid ß (Aß) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aß clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aß-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aß-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aß levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aß-binding monocytes may play a role in CNS Aß clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Disfunção Cognitiva , Progressão da Doença , Camundongos Transgênicos , Monócitos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Doença de Alzheimer/sangue , Humanos , Monócitos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Feminino , Idoso , Masculino , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/líquido cefalorraquidiano , Camundongos , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/metabolismo , Citometria de Fluxo , Modelos Animais de Doenças , Fagocitose , Pessoa de Meia-Idade
18.
Tuberk Toraks ; 72(3): 197-207, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39275932

RESUMO

Introduction: Platelets (PLT) and host systemic inflammatory response (SIR) are known to be effective in the aggregation of cancer cells and the formation of metastasis. There are studies pointing out to the prognostic efficacy of lymphocyte-monocyte ratio (LMR) showing SIR activation and mean platelet volume (MPV) values indicating platelet activation in various cancer types. We predict that easy-to-access hemogram parameters such as MPV, MPV/PLT, and LMR can be guiding in the clinical follow-up period of patients with epidermal growth factor receptor (EGFR) positive mutation and who received EGFR, tyrosine kinase inhibitor (TKI) in the first-line treatment in predicting the progression of the disease, predicting the survival time of the patients, and evaluating the response to treatment. Materials and Methods: The study is retrospective and included patients with stage III and stage IV pulmonary adenocarcinoma with positive EGFR mutations and for whom TKI was used in the first-line treatment between January 2011 and January 2021. MPV, MPV/PLT, and LMR values of the patients were calculated before treatment. Age, sex, comorbidity, smoking history, TNM stage, metastasis localizations, EGFR mutation types, TKI treatments used in first-line treatment, and MPV, MPV/PLT, and LMR values at the 1st month of treatment were recorded. With Kaplan-Meier, six-month, one-year, three-year, and five-year survival rates, average life expectancy, and 95% confidence intervals for these periods were calculated. Variables that may affect progression and overall survival (OS) were determined by performing univariate and multivariate Cox regression analysis. Result: One hundred and two patients were included in the study. The mean age of the patients was 64.30 ± 12.6 years. Eighty-four patients were in stage IV at the time of diagnosis. The expected mean progression-free survival (PFS) period of the cases was found to be 13.3 months. The mean life expectancy of the cases was found to be 35.1 months. Web-based Cutoff Finder algorithm written in the R program (http://molpath.charite.de/cutoff) was used to determine the ideal cut points for MPV, MPV/PLT, and LMR. The cut-off values were found to be 7.55 fL for MPV, 0.251 for MPV/PLT, and 2.615 for LMR, respectively. In univariate Cox regression analysis, LMR level lower than 2.615 increased the rate of progression 1.747 times (95% confidence interval: 1.129-2.705) and the death rate 2.056 times (95% confidence interval: 1.217-3.475) (p= 0.012, p= 0.007). The mean PFS LMR cut-off value was 10.3 months, and 15.3 months, and mean OS durations were 25.1 months and 40.8 months for the groups with low and high cut-off values respectively (p= 0.011, p= 0.006 log-rank test). According to the results of multivariate Cox regression analysis, MPV/PLT < 0.251, smoking, presence of pleural and adrenal metastases, and gefitinib treatment were independent factors in determining PFS. The independent factors determining OS in multivariate Cox regression analysis were being male, platelet increase, MPV > 7.55, gefitinib treatment, and smoking. Conclusions: MPV, MPV/PLT, and LMR are potential biomarkers that can be used for the clinical follow-up of lung ADC patients receiving EGFR-TKI treatment.


Assuntos
Adenocarcinoma de Pulmão , Receptores ErbB , Neoplasias Pulmonares , Volume Plaquetário Médio , Inibidores de Proteínas Quinases , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/patologia , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Prognóstico , Mutação , Monócitos , Plaquetas , Linfócitos
19.
JCI Insight ; 9(17)2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39253970

RESUMO

HIV-associated neurocognitive impairment (HIV-NCI) affects 15%-50% of people with HIV (PWH), despite viral suppression with antiretroviral therapy (ART). HIV neuropathogenesis is mediated, in part, by transmigration of infected CD14+CD16+ monocytes across the blood-brain barrier (BBB) into the central nervous system (CNS). In the CNS, CD14+CD16+ monocytes contribute to infection and activation of parenchymal cells, resulting in production of neurotoxic viral and host factors that cause neuronal damage. Mechanisms by which CD14+CD16+ monocytes contribute to HIV-NCI have not been characterized in a study population of PWH on ART without contribution from confounders that affect cognition (e.g., substance use, hepatitis C virus coinfection). We assessed cognitive function, PBMC transmigration across the BBB, and neuronal health markers in a well-defined cohort of 56 PWH on ART using stringent criteria to eliminate confounding factors. We demonstrated that PWH on ART with HIV-NCI have significantly increased transmigration of their CD14+CD16+ monocytes across the BBB compared with those with normal cognition. We showed that hypertension and diabetes may be effect modifiers on the association between CD14+CD16+ monocyte transmigration and cognition. This study underscored the persistent role of CD14+CD16+ monocytes in HIV-NCI, even in PWH with viral suppression, suggesting them as potential targets for therapeutic interventions.


Assuntos
Barreira Hematoencefálica , Infecções por HIV , Receptores de Lipopolissacarídeos , Monócitos , Receptores de IgG , Humanos , Barreira Hematoencefálica/metabolismo , Receptores de IgG/metabolismo , Monócitos/metabolismo , Monócitos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/metabolismo , Adulto , Proteínas Ligadas por GPI/metabolismo , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/metabolismo
20.
Nat Commun ; 15(1): 7863, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251592

RESUMO

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.


Assuntos
Interleucina-10 , Macrófagos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Cicatrização , Animais , Linfócitos T Reguladores/imunologia , Cicatrização/imunologia , Interleucina-10/metabolismo , Interleucina-10/genética , Humanos , Camundongos , Macrófagos/imunologia , Masculino , Monócitos/imunologia , Pele/imunologia , Interferon gama/metabolismo , Interferon gama/imunologia , Feminino
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