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1.
Ophthalmology ; 131(10): 1185-1195, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38703795

RESUMO

PURPOSE: Defining how the in vivo immune status of peripheral tissues is shaped by the external environment has remained a technical challenge. We recently developed Functional in vivo confocal microscopy (Fun-IVCM) for dynamic, longitudinal imaging of corneal immune cells in living humans. This study investigated the effect of seasonal-driven environmental factors on the morphodynamic features of human corneal immune cell subsets. DESIGN: Longitudinal, observational clinical study. PARTICIPANTS: Sixteen healthy participants (aged 18-40 years) attended 2 visits in distinct seasons in Melbourne, Australia (Visit 1, November-December 2021 [spring-summer]; Visit 2, April-June 2022 [autumn-winter]). METHODS: Environmental data were collected over each period. Participants underwent ocular surface examinations and corneal Fun-IVCM (Heidelberg Engineering). Corneal scans were acquired at 5.5 ± 1.5-minute intervals for up to 5 time points. Time-lapse Fun-IVCM videos were created to analyze corneal immune cells, comprising epithelial T cells and dendritic cells (DCs), and stromal macrophages. Tear cytokines were analyzed using a multiplex bead-based immunoassay. MAIN OUTCOME MEASURES: Difference in the density, morphology, and dynamic parameters of corneal immune cell subsets over the study periods. RESULTS: Visit 1 was characterized by higher temperature, lower humidity, and higher air particulate and pollen levels compared with Visit 2. Clinical ocular surface parameters and the density of immune cell subsets were similar across visits. At Visit 1 , corneal epithelial DCs were larger, with a lower dendrite probing speed (0.38 ± 0.21 vs. 0.68 ± 0.33 µm/min; P < 0.001) relative to Visit 2; stromal macrophages were more circular and had less dynamic activity (Visit 1, 7.2 ± 1.9 vs. Visit 2, 10.3 ± 3.7 dancing index; P < 0.001). Corneal T cell morphodynamics were unchanged across periods. Basal tear levels of interleukin 2 and CXCL10 were relatively lower during spring-summer. CONCLUSIONS: This study identifies that the in vivo morphodynamics of innate corneal immune cells (DCs, macrophages) are modified by environmental factors, but such effects are not evident for adaptive immune cells (T cells). The cornea is a potential in vivo window to investigate season-dependent environmental influences on the human immune system. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Assuntos
Imunidade Adaptativa , Córnea , Imunidade Inata , Estações do Ano , Humanos , Masculino , Adulto , Feminino , Adulto Jovem , Adolescente , Imunidade Inata/fisiologia , Córnea/imunologia , Células Dendríticas/imunologia , Microscopia Confocal , Citocinas/metabolismo , Lágrimas , Linfócitos T/imunologia , Microscopia Intravital , Macrófagos/imunologia , Voluntários Saudáveis
2.
J Neuroinflammation ; 21(1): 68, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500151

RESUMO

BACKGROUND: Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remodeling and repair. However, these phagocytes also contribute to chronic inflammation in degenerated retinas, yet the precise coordination of immune response to retinal damage remains elusive. Recent investigations have demonstrated that phagocytic cells can produce extracellular traps (ETs), which are a source of self-antigens that alter the immune response, which can potentially lead to tissue injury. METHODS: Innovations in experimental systems facilitate real-time exploration of immune cell interactions and dynamic responses. We integrated in vivo imaging with ultrastructural analysis, transcriptomics, pharmacological treatments, and knockout mice to elucidate the role of phagocytes and their modulation of the local inflammatory response through extracellular traps (ETs). Deciphering these mechanisms is essential for developing novel and enhanced immunotherapeutic approaches that can redirect a specific maladaptive immune response towards favorable wound healing in the retina. RESULTS: Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair and inflammation. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. We demonstrate that macrophages/monocytes, when recruited in the retina, release chromatin and granular proteins, forming ETs. Furthermore, the pharmacological inhibition of ETosis support retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, the absence of ETosis reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to be restricted primarily in the superficial capillary plexus instead of reaching the damaged photoreceptor layer. CONCLUSIONS: Our data offer novel insights into innate immunity's role in responding to retinal damage and potentially help developing innovative immunotherapeutic approaches that can shift the immune response from maladaptive to beneficial for retinal regeneration.


Assuntos
Armadilhas Extracelulares , Degeneração Retiniana , Animais , Camundongos , Macrófagos/metabolismo , Degeneração Retiniana/metabolismo , Imunidade Inata/fisiologia , Inflamação/metabolismo , Camundongos Knockout , Lasers
3.
Front Immunol ; 14: 1260705, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37781382

RESUMO

The imbalance of immune response plays a crucial role in the development of diseases, including glioblastoma. It is essential to comprehend how the innate immune system detects tumors and pathogens. Endosomal and cytoplasmic sensors can identify diverse cancer cell antigens, triggering the production of type I interferon and pro-inflammatory cytokines. This, in turn, stimulates interferon stimulating genes, enhancing the presentation of cancer antigens, and promoting T cell recognition and destruction of cancer cells. While RNA and DNA sensing of tumors and pathogens typically involve different receptors and adapters, their interaction can activate adaptive immune response mechanisms. This review highlights the similarity in RNA and DNA sensing mechanisms in the innate immunity of both tumors and pathogens. The aim is to enhance the anti-tumor innate immune response, identify regions of the tumor that are not responsive to treatment, and explore new targets to improve the response to conventional tumor therapy and immunotherapy.


Assuntos
Interferon Tipo I , Neoplasias , Humanos , Transdução de Sinais , Imunidade Inata/fisiologia , Imunidade Adaptativa , DNA , RNA
4.
Front Cell Infect Microbiol ; 13: 1269329, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37900310

RESUMO

Background: Influenza A virus (IAV) infection poses a persistent global health challenge, necessitating a nuanced grasp of host immune responses for optimal interventions. While the interplay between aging, immunosenescence, and IAV is recognized as key in severe lower respiratory tract infections, the role of specific patient attributes in shaping innate immune reactions and inflammasome activity during IAV infection remains under-investigated. In this study, we utilized an ex vivo infection model of human lung tissues with H3N2 IAV to discern relationships among patient demographics, IAV nucleoprotein (NP) expression, toll-like receptor (TLR) profiles, PD-1/PD-L1 markers, and cytokine production. Methods: Our cohort consisted of thirty adult patients who underwent video-assisted thoracoscopic surgery during 2018-2019. Post-surgical lung tissues were exposed to H3N2 IAV for ex vivo infections, and the ensuing immune responses were profiled using flow cytometry. Results: We observed pronounced IAV activity within lung cells, as indicated by marked NP upregulation in both epithelial cells (P = 0.022) and macrophages (P = 0.003) in the IAV-exposed group relative to controls. Notably, interleukin-2 levels correlated with variations in TLR1 expression on epithelial cells and PD-L1 markers on macrophages. Age emerged as a modulating factor, dampening innate immune reactions, as evidenced by reduced interleukin-2 and interferon-γ concentrations (both adjusted P < 0.05). Intriguingly, a subset of participants with pronounced tumor necrosis factor-alpha post-mock infection (Cluster 1) showed attenuated cytokine responses in contrast to their counterparts in Cluster 2 and Cluster 3 (all adjusted P < 0.05). Individuals in Cluster 2, characterized by a low post-mock infection NP expression in macrophages, exhibited reduced variations in both NP and TLR1-3 expressions on these cells and a decreased variation in interleukin-2 secretion in comparison to their Cluster 3 counterparts, who were identified by their elevated NP macrophage expression (all adjusted P < 0.05). Conclusion: Our work elucidates the multifaceted interplay of patient factors, innate immunity, and inflammasome responses in lung tissues subjected to ex vivo H3N2 IAV exposure, reflecting real-world lower respiratory tract infections. While these findings provide a foundation for tailored therapeutic strategies, supplementary studies are requisite for thorough validation and refinement.


Assuntos
Vírus da Influenza A , Influenza Humana , Adulto , Humanos , Inflamassomos , Interleucina-2 , Antígeno B7-H1 , Vírus da Influenza A Subtipo H3N2 , Receptor 1 Toll-Like , Imunidade Inata/fisiologia , Pulmão/patologia , Citocinas
5.
Front Immunol ; 14: 1161606, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37033937

RESUMO

Endometriosis is closely associated with ectopic focal inflammation and immunosuppressive microenvironment. Multiple types of pattern recognition receptors (PRRs) are present in the innate immune system, which are able to detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in both intracellular and external environments. However, the exact role of PRRs in endometriosis and the underlying molecular mechanism are unclear. PRRs are necessary for the innate immune system to identify and destroy invasive foreign infectious agents. Mammals mainly have two types of microbial recognition systems. The first one consists of the membrane-bound receptors, such as toll-like receptors (TLRs), which recognize extracellular microorganisms and activate intracellular signals to stimulate immune responses. The second one consists of the intracellular PRRs, including nod-like receptors (NLRs) and antiviral proteins retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) with helix enzyme domain. In this review, we mainly focus on the key role of PRRs in the pathological processes associated with endometriosis. PRRs recognize PAMPs and can distinguish pathogenic microorganisms from self, triggering receptor ligand reaction followed by the stimulation of host immune response. Activated immune response promotes the transmission of microbial infection signals to the cells. As endometriosis is characterized by dysregulated inflammation and immune response, PRRs may potentially be involved in the activation of endometriosis-associated inflammation and immune disorders. Toll-like receptor 2 (TLR2), toll-like receptor 3 (TLR3), toll-like receptor 4 (TLR4), nod-like receptor family caspase activation and recruitment domain (CARD) domain containing 5 (NLRC5), nod-like receptor family pyrin domain containing 3 (NLRP3), and c-type lectin receptors (CLRs) play essential roles in endometriosis development by regulating immune and inflammatory responses. Absent in melanoma 2 (AIM2)-like receptors (ALRs) and retinoic acid-inducible gene I-like receptors (RLRs) may be involved in the activation of endometriosis-associated immune and inflammation disorders. PRRs, especially TLRs, may serve as potential therapeutic targets for alleviating pain in endometriosis patients. PRRs and their ligands interact with the innate immune system to enhance inflammation in the stromal cells during endometriosis. Thus, targeting PRRs and their new synthetic ligands may provide new therapeutic options for treating endometriosis.


Assuntos
Endometriose , Melanoma , Animais , Feminino , Humanos , Imunidade Inata/fisiologia , Transdução de Sinais , Ligantes , Moléculas com Motivos Associados a Patógenos , Receptores de Reconhecimento de Padrão/metabolismo , Receptores Toll-Like/metabolismo , Inflamação , Proteínas NLR/metabolismo , Proteínas de Transporte/metabolismo , Tretinoína/metabolismo , Mamíferos/metabolismo , Microambiente Tumoral
6.
Front Immunol ; 14: 1118483, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36776864

RESUMO

Innate lymphoid cells (ILCs) are important subsets of innate immune cells that regulate mucosal immunity. ILCs include natural killer cells, innate lymphoid cells-1 (ILC1s), ILC2s, and ILC3s, which have extremely important roles in the immune system. In this review, we summarize the regulation of mRNA stability mediated through various factors in ILCs (e.g., cytokines, RNA-binding proteins, non-coding RNAs) and their roles in mediating functions in different ILC subsets. In addition, we discuss potential therapeutic targets for diseases such as chronic obstructive pulmonary disease, cancer, and pulmonary fibrosis by regulation of mRNA stability in ILCs, which may provide novel directions for future clinical research.


Assuntos
Citocinas , Imunidade Inata , Imunidade Inata/fisiologia , Citocinas/metabolismo , Células Matadoras Naturais , Estabilidade de RNA
7.
J Endocrinol ; 257(1)2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36688876

RESUMO

Inflammation is part of the body's innate immune response and is an essential process that not only defends against harmful bacteria and pathogens but also plays a key role in the maintenance and repair of tissues. Under pathological conditions, there is bilateral crosstalk between immune regulation and aberrant metabolism resulting in persistent inflammation in the absence of infection. This phenomenon is referred to as sterile metabolic inflammation (metainflammation) and occurs if the initiating stimulus is not removed or if the resolution process is disrupted. Disruption of this tightly regulated immune response and its failure to resolve as is evident in metabolic disorders is not only associated with disease progression but also leads to immune senescence and should not be neglected in the clinical management of patients. This review gives an overview of the mechanisms underlying chronic metabolic inflammation, the aberrant metabolic activation of innate immune cells (neutrophils, macrophages, mast cells, dendritic cells), and its role in disease progression using obesity-diabetes as a prime example. Addressing the underlying subclinical metabolic inflammation in addition to achieving glucose control may contribute significantly towards therapeutic interventions aimed at preventing the onset of co-morbidities in diabetic patients.


Assuntos
Imunidade Inata , Inflamação , Humanos , Inflamação/metabolismo , Imunidade Inata/fisiologia , Macrófagos/metabolismo , Progressão da Doença
8.
Sci China Life Sci ; 66(2): 283-297, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36115893

RESUMO

B-cell lymphoma 10 (Bcl10) is a scaffolding protein that functions as an upstream regulator of NF-κB signaling by forming a complex with Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) and CARD-coiled coil protein family. This study showed that Bcl10 was involved in type I interferon (IFN) expression in response to DNA virus infection and that Bcl10-deficient mice were more susceptible to Herpes simplex virus 1 (HSV-1) infection than control mice. Mechanistically, DNA virus infection can trigger Bcl10 recruitment to the STING-TBK1 complex, leading to Bcl10 phosphorylation by TBK1. The phosphorylated Bcl10 undergoes droplet-like condensation and forms oligomers, which induce TBK1 phosphorylation and translocation to the perinuclear region. The activated TBK1 phosphorylates IRF3, which induces the expression of type I IFNs. This study elucidates that Bcl10 induces an innate immune response by undergoing droplet-like condensation and participating in signalosome formation downstream of the cGAS-STING pathway.


Assuntos
Proteína 10 de Linfoma CCL de Células B , Imunidade Inata , Animais , Camundongos , Proteína 10 de Linfoma CCL de Células B/genética , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Imunidade Inata/fisiologia , NF-kappa B/metabolismo , Fosforilação
9.
Immunobiology ; 227(5): 152262, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36049365

RESUMO

The oncogene ABL1 plays an important role in various cancers, while its roles remain unclear in pneumonia. This study aims to investigate the roles of ABL1 in pneumonia and the underlying mechanisms. RNA sequencing was used to determine the expressions of multiple kinases in the PBMCs. A series of overexpression and knockout cell lines were constructed. Besides, an intranasal lung infection mouse model was pre-treated with asciminb. ELISAs and qPCR were used to determine the levels of target genes. In addition, STRING Interaction Network and Immunoblotting assays were used to determine the interaction between target proteins. An elevation in ABL1 was observed in the infant with Ecoli pneumonia. ABL1 was positively correlated to the levels of inflammatory cytokines and the activation of the NF-kB pathways. In vivo data demonstrated that the inhibition of ABL1 suppressed the inflammatory cytokines, reduced the lung bacterial burden, and ameliorated the lung injury score. ABL1 inhibited the phosphorylation of IκBα and p38 and regulated the ubiquitination of TRAF6. ABL1 regulates the inflammatory response in pneumonia in part by the regulation of MAPK and NF-κB pathways and TRAF6 ubiquitination.


Assuntos
Imunidade Inata , NF-kappa B , Proteínas Proto-Oncogênicas c-abl , Fator 6 Associado a Receptor de TNF , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata/genética , Imunidade Inata/fisiologia , Inflamação/genética , Inflamação/metabolismo , Camundongos , NF-kappa B/metabolismo , Oncogenes , Proteínas Proto-Oncogênicas c-abl/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Ubiquitinação
10.
Front Immunol ; 13: 824263, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774779

RESUMO

Members of the innate immune system, innate lymphoid cells (ILCs), encompass five major populations (Natural Killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells) whose functions include defense against pathogens, surveillance of tumorigenesis, and regulation of tissue homeostasis and remodeling. ILCs are present in the uterine environment of humans and mice and are dynamically regulated during the reproductive cycle and pregnancy. These cells have been repurposed to support pregnancy promoting maternal immune tolerance and placental development. To accomplish their tasks, immune cells employ several cellular and molecular mechanisms. They have the capacity to remember a previously encountered antigen and mount a more effective response to succeeding events. Memory responses are not an exclusive feature of the adaptive immune system, but also occur in innate immune cells. Innate immune memory has already been demonstrated in monocytes/macrophages, neutrophils, dendritic cells, and ILCs. A population of decidual NK cells characterized by elevated expression of NKG2C and LILRB1 as well as a distinctive transcriptional and epigenetic profile was found to expand during subsequent pregnancies in humans. These cells secrete high amounts of interferon-γ and vascular endothelial growth factor likely favoring placentation. Similarly, uterine ILC1s in mice upregulate CXCR6 and expand in second pregnancies. These data provide evidence on the development of immunological memory of pregnancy. In this article, the characteristics, functions, and localization of ILCs are reviewed, emphasizing available data on the uterine environment. Following, the concept of innate immune memory and its mechanisms, which include epigenetic changes and metabolic rewiring, are presented. Finally, the emerging role of innate immune memory on reproduction is discussed. Advances in the comprehension of ILC functions and innate immune memory may contribute to uncovering the immunological mechanisms underlying female fertility/infertility, placental development, and distinct outcomes in second pregnancies related to higher birth weight and lower incidence of complications.


Assuntos
Imunidade Inata , Fator A de Crescimento do Endotélio Vascular , Animais , Feminino , Imunidade Inata/fisiologia , Células Matadoras Naturais , Camundongos , Placenta , Gravidez , Reprodução
11.
Biomolecules ; 12(5)2022 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-35625664

RESUMO

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving adaptation.


Assuntos
Imunidade Inata , Inflamação , Humanos , Imunidade Inata/fisiologia , Transdução de Sinais
12.
Front Immunol ; 13: 812774, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309296

RESUMO

Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.


Assuntos
Transdução de Sinais , Receptores Toll-Like , Imunidade Adaptativa , Imunidade Celular , Imunidade Inata/fisiologia
13.
Int Immunopharmacol ; 107: 108708, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35306281

RESUMO

Innate and adaptive immunity synergistically contribute to an effective anti-tumor response. Therapeutics targeting T cells, such as immune checkpoint inhibitors and engineered chimeric antigen receptor (CAR) T cells have shown promising effects in patients with hematologic malignancies. These strategies aim to strengthen T cell activation, proliferation, survival, and/or effector function by altering T cell receptor (TCR) signaling, co-stimulation, and cytokine gene expression. Toll-like receptors (TLRs) are primarily expressed by innate immune cells and are known to recognize pathogen-associated molecular patterns (PAMPs). However, increasing studies have highlighted their intrinsic contribution to T cell-mediated anti-tumor responses. Here, we have summarized the advances in our understanding of the ability of different types of TLRs and their downstream signaling pathways to activate anti-tumor immunity in T cells. Additionally, we discuss the potential for TLR agonists in improving the therapeutic effects when used in combination with other treatments.


Assuntos
Neoplasias , Linfócitos T , Imunidade Adaptativa , Humanos , Imunidade Inata/fisiologia , Ativação Linfocitária , Neoplasias/terapia , Transdução de Sinais , Receptores Toll-Like
14.
Int J Mol Sci ; 23(3)2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35163253

RESUMO

Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)-including phagocytes and viable tumour cells-and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with "double-edged" consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.


Assuntos
Apoptose/fisiologia , Neoplasias/patologia , Animais , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Humanos , Imunidade Inata/fisiologia , Fagócitos/fisiologia , Microambiente Tumoral/fisiologia
15.
Int J Mol Sci ; 23(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216355

RESUMO

It is now well understood that the bone marrow (BM) compartment can sense systemic inflammatory signals and adapt through increased proliferation and lineage skewing. These coordinated and dynamic alterations in responding hematopoietic stem and progenitor cells (HSPCs), as well as in cells of the bone marrow niche, are increasingly viewed as key contributors to the inflammatory response. Growth factors, cytokines, metabolites, microbial products, and other signals can cause dysregulation across the entire hematopoietic hierarchy, leading to lineage-skewing and even long-term functional adaptations in bone marrow progenitor cells. These alterations may play a central role in the chronicity of disease as well as the links between many common chronic disorders. The possible existence of a form of "memory" in bone marrow progenitor cells is thought to contribute to innate immune responses via the generation of trained immunity (also called innate immune memory). These findings highlight how hematopoietic progenitors dynamically adapt to meet the demand for innate immune cells and how this adaptive response may be beneficial or detrimental depending on the context. In this review, we will discuss the role of bone marrow progenitor cells and their microenvironment in shaping the scope and scale of the immune response in health and disease.


Assuntos
Medula Óssea/patologia , Células-Tronco Hematopoéticas/patologia , Inflamação/patologia , Nicho de Células-Tronco/fisiologia , Células-Tronco/patologia , Animais , Doença Crônica , Humanos , Imunidade Inata/fisiologia
16.
Med Oncol ; 39(5): 58, 2022 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-35150340

RESUMO

High-mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that (1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, (2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and (3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called "cold" to "immune-inflamed" or "hot" and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.


Assuntos
Proteína HMGB1/metabolismo , Imunidade Inata/fisiologia , Inflamação/metabolismo , Melanoma/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Proteína HMGB1/genética , Humanos , Melanoma/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Microambiente Tumoral/genética
17.
Am J Reprod Immunol ; 87(1): e13502, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34592011

RESUMO

PROBLEM: Innate lymphoid cells (ILCs), a recently discovered family of innate immune cells, are responsible for the early immune response, and control both innate and adapted immune system via cytokine secretion. The role of ILCs in endometriosis has not been investigated; therefore, here, we aimed to investigate how the proportion of ILCs changes in endometriosis. METHOD OF STUDY: The percentage of each ILC group in CD45+ cells was examined in the peripheral blood, peritoneal fluid, endometrium, and ovarian endometrioma obtained from women with and without endometriosis (ERB-C-1216) using flow cytometry. RESULTS: Specimens were obtained from 19 women with endometriosis and 15 without endometriosis. In the endometrium, patients with endometriosis had lower proportion of ILC2 and 3 compared to control specimens (ILC2: .02±.01% vs .07±.03%; P < .05, ILC3: .31±.14% vs 1.10±.93%; P < .05). There was no significant change in the peripheral blood or the peritoneal fluid between the two groups. Additionally, ovarian endometrioma increased the proportion of ILCs (ILC1: .92±1.12%, ILC2: .08±.08%, ILC3: .70±.39%) compared to the endometrium samples of patients with endometriosis each with P < .05. Immunohistochemistry of IL-1ß and IL-23, which are ILC3-inducing factors, showed no significant change in the H-score of the epithelium of the two groups, but a significant increase was found in ovarian endometrioma. CONCLUSION: The proportion of ILC2 and 3 was reduced in the endometrium of patients with endometriosis, and ILCs were increased in ovarian endometrioma. Our findings may indicate a new immunological approach to understand the pathophysiology of endometriosis.


Assuntos
Endometriose/imunologia , Endométrio/imunologia , Imunidade Inata/fisiologia , Linfócitos/patologia , Adulto , Citocinas/imunologia , Endometriose/patologia , Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
18.
Handb Exp Pharmacol ; 276: 133-159, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34505203

RESUMO

Mast cells (MCs) distribute to interface tissues with environment, such as skin, airway, and gut mucosa, thereby functioning as the sentinel against invading allergens and pathogens. To respond to and exclude these external substances promptly, MCs possess granules containing inflammatory mediators, including heparin, proteases, tumor necrosis factor, and histamine, and produce these mediators as a consequence of degranulation within minutes of activation. As a delayed response to external substances, MCs de novo synthesize inflammatory mediators, such as cytokines and chemokines, by sensing pathogen- and damage-associated molecular patterns through their pattern recognition receptors, including Toll-like receptors (TLRs). A substantial number of studies have reported immune responses by MCs through surface TLR signaling, particularly TLR2 and TLR4. However, less attention has been paid to immune responses through nucleic acid-recognizing intracellular TLRs. Among intracellular TLRs, human and rodent MCs express TLR3, TLR7, and TLR9, but not TLR8. Some virus infections modulate intracellular TLR expression in MCs. MC-derived mediators, such as histamine, cysteinyl leukotrienes, LL-37, and the granulocyte-macrophage colony-stimulating factor, have also been reported to modulate intracellular TLR expression in an autocrine and/or paracrine fashion. Synthetic ligands for intracellular TLRs and some viruses are sensed by intracellular TLRs of MCs, leading to the production of inflammatory cytokines and chemokines including type I interferons. These MC responses initiate and facilitate innate responses and the subsequent recruitment of additional innate effector cells. MCs also associate with the regulation of adaptive immunity. In this overview, the expression of intracellular TLRs in MCs and the recognition of pathogens, including viruses, by intracellular TLRs in MCs were critically evaluated.


Assuntos
Histamina , Mastócitos , Imunidade Adaptativa , Quimiocinas , Citocinas , Humanos , Imunidade Inata/fisiologia , Mastócitos/metabolismo , Receptores Toll-Like
19.
FEBS J ; 289(14): 3967-3981, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-33837637

RESUMO

In the last decade, innate lymphoid cells (ILCs) have become established as important players in different areas such as tissue homeostasis, integrity of mucosal barriers and regulation of inflammation. While most of the early work on ILCs was based on murine studies, our knowledge on human ILCs is rapidly accumulating, opening novel perspectives towards the translation of ILC biology into the clinic. In this State-of-the-Art Review, we focus on the current knowledge of these most recently discovered members of the lymphocyte family and highlight their role in three major burdens of humanity: infectious diseases, cancer, and allergy and/or autoimmunity. IL-22-producing type 3 innate lymphoid cells (ILC3s) have become established as important players at the interface between gut epithelia and intestinal microbiome and are implicated in protection from inflammatory bowel disease, the control of graft-versus-host disease and intestinal graft rejection. In contrast, type 2 innate lymphoid cells (ILC2s) exert pro-inflammatory functions and contribute to the pathology of asthma and allergy, which has already been started to be pharmacologically targeted. The contribution of ILCs to the control of viral infection constitutes another emerging topic. Finally, ILCs seem to play a dual role in cancer with beneficial and detrimental contributions depending on the clinical setting. The exploitation of the therapeutic potential of ILCs will constitute an exciting task in the foreseeable future.


Assuntos
Asma , Linfócitos , Animais , Biologia , Humanos , Imunidade Inata/fisiologia , Intestinos , Camundongos
20.
Int J Mol Sci ; 22(24)2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34948194

RESUMO

The innate immune system plays a pivotal role in the first line of host defense against infections and is equipped with patterns recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Several classes of PRRS, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) recognize distinct microbial components and directly activate immune cells. TLRs are transmembrane receptors, while NLRs and RLRs are intracellular molecules. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. The innate immune system also influences pathways involved in cancer immunosurveillance. Natural and synthetic agonists of TLRs, NLRs, or RLRs can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment, and are being explored as promising adjuvants in cancer immunotherapies. In this review, we provide a concise overview of TLRs, NLRs, and RLRs: their structure, functions, signaling pathways, and regulation. We also describe various ligands for these receptors and their possible application in treatment of hematopoietic diseases.


Assuntos
Proteína DEAD-box 58/imunologia , Proteínas NLR/imunologia , Receptores Toll-Like/imunologia , Animais , Proteína DEAD-box 58/metabolismo , Humanos , Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Fatores Imunológicos , Imunoterapia , Ligantes , Proteínas NLR/metabolismo , Transporte Proteico , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo
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