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1.
Aging (Albany NY) ; 15(1): 21-36, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36622277

RESUMO

Dietary restriction (DR) is a highly effective and reproducible intervention that prolongs longevity in many organisms. The molecular mechanism of action of DR is tightly connected with the immune system; however, the detailed mechanisms and effective downstream factors of immunity that mediate the beneficial effects of DR on aging remain unknown. Here, to investigate the immune signaling that mediates DR effects, we used Caenorhabditis elegans, which has been widely used in research, to understand the underlying molecular mechanisms of aging and immunity. We found that the F-box gene, fbxc-58, a regulator of the innate immune response, is a novel mediator of DR effects on extending the health span of C. elegans. fbxc-58 is upregulated by DR and is necessary for DR-induced lifespan extension and physical health improvement in C. elegans. Furthermore, through DR, fbxc-58 prevents disintegration of the mitochondrial network in body wall muscle during aging. We found that fbxc-58 is a downstream target of the ZIP-2 and PHA-4 transcription factors, the well-known DR mediator, and fbxc-58 extends longevity in DR through an S6 kinase-dependent pathway. We propose that the novel DR effector, fbxc-58, could provide a new mechanistic understanding of the effects of DR on healthy aging and elucidate the signaling mechanisms that link immunity and DR effects with aging.


Assuntos
Proteínas de Caenorhabditis elegans , Envelhecimento Saudável , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Restrição Calórica , Imunidade Inata/fisiologia
2.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430676

RESUMO

Research of the last decade has remarkably increased our understanding of innate lymphoid cells (ILCs). ILCs, in analogy to T helper (Th) cells and their cytokine and transcription factor profile, are categorized into three distinct populations: ILC1s express the transcription factor T-bet and secrete IFNγ, ILC2s depend on the expression of GATA-3 and release IL-5 and IL-13, and ILC3s express RORγt and secrete IL-17 and IL-22. Noteworthy, ILCs maintain a level of plasticity, depending on exposed cytokines and environmental stimuli. Furthermore, ILCs are tissue resident cells primarily localized at common entry points for pathogens such as the gut-associated lymphoid tissue (GALT). They have the unique capacity to initiate rapid responses against pathogens, provoked by changes of the cytokine profile of the respective tissue. Moreover, they regulate tissue inflammation and homeostasis. In case of intracellular pathogens entering the mucosal tissue, ILC1s respond by secreting cytokines (e.g., IFNγ) to limit the pathogen spread. Upon infection with helminths, intestinal epithelial cells produce alarmins (e.g., IL-25) and activate ILC2s to secrete IL-13, which induces differentiation of intestinal stem cells into tuft and goblet cells, important for parasite expulsion. Additionally, during bacterial infection ILC3-derived IL-22 is required for bacterial clearance by regulating antimicrobial gene expression in epithelial cells. Thus, ILCs can limit infectious diseases via secretion of inflammatory mediators and interaction with other cell types. In this review, we will address the role of ILCs during enteric infectious diseases.


Assuntos
Gastroenteropatias , Imunidade Inata , Linfócitos , Humanos , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/metabolismo , Citocinas/metabolismo , Imunidade Inata/fisiologia , Interleucina-13/metabolismo , Linfócitos/metabolismo , Gastroenteropatias/imunologia , Gastroenteropatias/microbiologia
3.
Front Immunol ; 13: 1014774, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275689

RESUMO

Innate lymphoid cells (ILCs) are a critical element of the innate immune system and are potent producers of pro-inflammatory cytokines. Recently, however, the production of the anti-inflammatory cytokine IL-10 has been observed in all ILC subtypes (ILC1s, ILC2s, and ILC3s) suggesting their ability to adopt a regulatory phenotype that serves to maintain lung and gut homeostasis. Other studies advocate a potential therapeutic role of these IL-10-expressing ILCs in allergic diseases such as asthma, colitis, and pancreatic islet allograft rejection. Herein, we review IL-10 producing ILCs, discussing their development, function, regulation, and immunotherapeutic potential through suppressing harmful inflammatory responses. Furthermore, we address inconsistencies in the literature regarding these regulatory IL-10 producing ILCs, as well as directions for future research.


Assuntos
Asma , Imunidade Inata , Humanos , Imunidade Inata/fisiologia , Linfócitos , Interleucina-10 , Citocinas
4.
Curr Opin Immunol ; 78: 102251, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36242870

RESUMO

The interferon-regulated kinase PKR (protein kinase RNA-activated) is a potent innate immune factor against a broad range of viruses. Being part of the integrated stress response (ISR), its restrictive effect is predominantly exerted by phosphorylating the eukaryotic translation-initiation factor eIF2, thereby turning it into an inhibitor of translation-initiation factor eIF2B. A plethora of viruses are known to evade the shutdown of cellular mRNA translation by interfering either with PKR activation or with eIF2 phosphorylation. Recently, a novel PKR evasion strategy was described: proteins from three taxonomically distinct RNA viruses allow for full PKR activation and eIF2 phosphorylation in the infected cell, but protect eIF2B from inhibition by phosphorylated eIF2, thus enabling mRNA translation in the presence of an activated ISR.


Assuntos
Fator de Iniciação 2B em Eucariotos , Fator de Iniciação 2 em Eucariotos , Imunidade Inata , Viroses , Humanos , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Imunidade Inata/genética , Imunidade Inata/fisiologia , Interferons , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , RNA Mensageiro , Viroses/genética , Viroses/imunologia , Viroses/metabolismo
5.
Nucleic Acids Res ; 50(19): 11093-11108, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36243958

RESUMO

Double-stranded DNA (dsDNA) is recognized as a danger signal by cyclic GMP-AMP synthase (cGAS), which triggers innate immune responses. cGAS activity must be properly regulated to maintain immune homeostasis. However, the mechanism by which cGAS activation is controlled remains to be better understood. In this study, we identified USP15 as a cGAS-interacting partner. USP15 promoted DNA-induced cGAS activation and downstream innate immune responses through a positive feedback mechanism. Specifically, USP15 deubiquitylated cGAS and promoted its activation. In the absence of DNA, USP15 drove cGAS dimerization and liquid condensation through the USP15 intrinsic disordered region (IDR), which prepared cGAS for a rapid response to DNA. Upon DNA stimulation, USP15 was induced to express and boost cGAS activation, functioning as an efficient amplifier in innate immune signal transduction. In summary, the positive role played by USP15-mediated cGAS activation may be a novel regulatory mechanism in the fine-tuning of innate immunity.


Assuntos
Imunidade Inata , Nucleotidiltransferases , Nucleotidiltransferases/metabolismo , Imunidade Inata/fisiologia , DNA/genética , Transdução de Sinais/genética
6.
Trends Neurosci ; 45(10): 733-748, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36075783

RESUMO

Neurodegenerative diseases are a major cause of death and disability worldwide and are influenced by many factors including age, genetics, and injuries. While these diseases are often thought to result from the accumulation and spread of aberrant proteins, recent studies have demonstrated that they can be shaped by the innate and adaptive immune system. Resident myeloid cells typically mount a sustained response to the degenerating CNS, but peripheral leukocytes such as T and B cells can also alter disease trajectories. Here, we review the sometimes-dichotomous roles played by immune cells during neurodegenerative diseases and explore how brain trauma can serve as a disease initiator or accelerant. We also offer insights into how failure to properly resolve a CNS injury might promote the development of a neurodegenerative disease.


Assuntos
Doenças Neurodegenerativas , Humanos , Sistema Imunitário , Imunidade Inata/fisiologia , Doenças Neurodegenerativas/metabolismo
7.
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
8.
J Exp Biol ; 225(17)2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35946379

RESUMO

Sublethal dehydration can cause negative physiological effects, but recent studies investigating the sub-lethal effects of dehydration on innate immune performance in reptiles have found a positive correlation between innate immune response and plasma osmolality. To investigate whether this is an adaptive trait that evolved in response to dehydration in populations inhabiting water-scarce environments, we sampled free-ranging cottonmouth snakes (n=26 adult cottonmouths) from two populations inhabiting contrasting environments in terms of water availability: Snake Key (n=12), an island with no permanent sources of fresh water, and Paynes Prairie (n=14), a flooded freshwater prairie. In addition to field surveys, we manipulated the hydration state of 17 cottonmouths (Paynes Prairie n=9, Snake Key n=8) in a laboratory setting and measured the response of corticosterone and innate immune performance to dehydration with the aim of identifying any correlation or trade-offs between them. We measured corticosterone of cottonmouths at a baseline level and then again following a 60 min stress test when at three hydration states: hydrated, dehydrated and rehydrated. We found that innate immune performance improved with dehydration and then returned to baseline levels within 48 h of rehydration, which agrees with previous research in reptiles. Despite the frequent exposure of cottonmouths on Snake Key to dehydrating conditions, we did not find cottonmouths inhabiting the island to show a greater magnitude or more prolonged immune response compared with cottonmouths from Paynes Prairie. We also found a positive association between dehydration and corticosterone values.


Assuntos
Agkistrodon , Crotalinae , Agkistrodon/fisiologia , Animais , Corticosterona , Desidratação/veterinária , Imunidade Inata/fisiologia , Serpentes/fisiologia , Água
9.
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
10.
WIREs Mech Dis ; 14(5): e1567, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35674186

RESUMO

In a world filled with microbes, some posing a threat to our body, our immune system is key to living a healthy life. The innate immune system is made of various cell types that act to guard our bodies. Unlike the adaptive immune system that has a specific response, our innate immune system encompasses cells that elicit unspecific immune responses, triggered whenever the right signals are detected. Our understanding of immunity started with the concept of our immune system only responding to "nonself" like the pathogens that invade our body. However, over the past few decades, we have learned that the immune system is more than an on/off switch that recognizes nonself. The innate immune system regularly patrols our bodies for pathogens and tissue damage. Our innate immune system not only seeks to resolve infection but also repair tissue injury, through phagocytosing debris and initiating the release of growth factors. Recently, we are starting to see that it is not just recognizing danger, our innate immune system plays a crucial role in repair. Innate immune cells phenotypically change during repair. In the context of severe injury or trauma, our innate immune system is modified quite drastically to help repair, resulting in reduced infection control. Moreover, these changes in immune cell function can be modified by sex as a biological variable. From past to present, in this overview, we provide a summary of the innate immune cells and pathways in infection and tissue repair. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology.


Assuntos
Sistema Imunitário , Imunidade Inata , Imunidade Inata/fisiologia , Fagocitose
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.
Mediators Inflamm ; 2022: 5344085, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35509434

RESUMO

Skin wounds and compromised wound healing are major concerns for the public. Although skin wound healing has been studied for decades, the molecular and cellular mechanisms behind the process are still not completely clear. The systemic responses to trauma involve the body's inflammatory and immunomodulatory cellular and humoral networks. Studies over the years provided essential insights into a complex and dynamic immunity during the cutaneous wound healing process. This review will focus on innate cell populations involved in the initial phase of this orchestrated process, including innate cells from both the skin and the immune system.


Assuntos
Imunidade Inata , Cicatrização , Imunidade Inata/fisiologia , Imunomodulação , Pele , Cicatrização/fisiologia
13.
Curr Osteoporos Rep ; 20(3): 186-193, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35507293

RESUMO

PURPOSE OF REVIEW: To review the mechanisms by which vitamin D and its metabolites regulate the immune system to facilitate the ability of the body to prevent and/or treat SARS-CoV2 and other respiratory infections and encourage further research into the role that vitamin D supplementation plays in preventing/treating such infections. RECENT FINDINGS: Vitamin D deficiency is associated with an increased risk of SARS-CoV2 and other respiratory infections. Clinical trials in general demonstrate that correction of vitamin D deficiency reduces the risk of hospitalization, ICU admission, and death from SARS-CoV2 infection. The airway epithelium and alveolar macrophages express the enzyme, CYP27B1, that produces the active metabolite of vitamin D, 1,25(OH)2D, and the vitamin D receptor, VDR. Vitamin D and its metabolites promote the innate immune response, which provides the first line of defense against viral and bacterial infections while restricting the adaptive immune response, which if unchecked promotes the inflammatory response leading to the acute respiratory distress syndrome and death. The rationale for treating vitamin D deficiency to reduce the risk of SARS-CoV2 infection and supplementing patients with vitamin D early in the course of SARS-CoV2 infection rests primarily on the ability of vitamin D metabolites to promote an effective immune response to the infection.


Assuntos
COVID-19 , Deficiência de Vitamina D , Humanos , Imunidade Inata/fisiologia , RNA Viral , SARS-CoV-2 , Vitamina D/metabolismo , Deficiência de Vitamina D/complicações
14.
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
15.
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
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.
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
18.
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
19.
Cell Rep ; 38(4): 110286, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35081354

RESUMO

Selective autophagy is a catabolic route that turns over specific cellular material for degradation by lysosomes, and whose role in the regulation of innate immunity is largely unexplored. Here, we show that the apical kinase of the Drosophila immune deficiency (IMD) pathway Tak1, as well as its co-activator Tab2, are both selective autophagy substrates that interact with the autophagy protein Atg8a. We also present a role for the Atg8a-interacting protein Sh3px1 in the downregulation of the IMD pathway, by facilitating targeting of the Tak1/Tab2 complex to the autophagy platform through its interaction with Tab2. Our findings show the Tak1/Tab2/Sh3px1 interactions with Atg8a mediate the removal of the Tak1/Tab2 signaling complex by selective autophagy. This in turn prevents constitutive activation of the IMD pathway in Drosophila. This study provides mechanistic insight on the regulation of innate immune responses by selective autophagy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Autofagia/imunologia , Proteínas de Drosophila/imunologia , Imunidade Inata/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , MAP Quinase Quinase Quinases/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Transdução de Sinais/imunologia
20.
Nat Commun ; 13(1): 17, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013162

RESUMO

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; specifically, the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. Two different types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is an RNA virus, and microsporidia, which comprise a phylum of fungal pathogens. Despite their molecular differences, these pathogens induce a common host transcriptional response called the intracellular pathogen response (IPR). Here we show that zip-1 is an IPR regulator that functions downstream of all known IPR-activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor, and we show that zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is at least partially required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for triggers of the IPR, and that this transcription factor has a protective function against intracellular pathogen infection in C. elegans.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Caenorhabditis elegans , Enterócitos , Interações Hospedeiro-Patógeno/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/virologia , Proteínas de Caenorhabditis elegans/imunologia , Proteínas de Caenorhabditis elegans/metabolismo , Enterócitos/imunologia , Enterócitos/microbiologia , Enterócitos/virologia , Imunidade Inata/fisiologia , Intestinos/microbiologia , Intestinos/virologia , Invertebrados/imunologia , Microsporídios/patogenicidade , Vírus de RNA/patogenicidade
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