scholarly journals Unraveling the Molecular Mechanism of Immunosenescence in Drosophila

2018 ◽  
Vol 19 (9) ◽  
pp. 2472 ◽  
Author(s):  
Kyung-Jin Min ◽  
Marc Tatar
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Growth Factor ◽  
Molecular Biology ◽  
System Performance ◽  
Aging Process ◽  
Feedback System ◽  
Genetic Dissection ◽  
System Degeneration

A common feature of the aging process is a decline in immune system performance. Extensive research has sought to elucidate how changes in adaptive immunity contribute to aging and to provide evidence showing that changes in innate immunity have an important role in the overall decline of net immune function. Drosophila is an emerging model used to address questions related to immunosenescence via research that integrates its capacity for genetic dissection of aging with groundbreaking molecular biology related to innate immunity. Herein, we review information on the immunosenescence of Drosophila and suggest its possible mechanisms that involve changes in insulin/IGF(insulin-like growth factor)-1 signaling, hormones such as juvenile hormone and 20-hydroxyecdysone, and feedback system degeneration. Lastly, the emerging role of microbiota on the regulation of immunity and aging in Drosophila is discussed.

scholarly journals Toll-like receptor-mediated innate immunity against herpesviridae infection: a current perspective on viral infection signaling pathways

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wenjin Zheng ◽  
Qing Xu ◽  
Yiyuan Zhang ◽  
Xiaofei E ◽  
Wei Gao ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Signaling Pathways ◽  
Critical Role ◽  
Innate Immune ◽  
Host Cells ◽  
Main Body ◽  
Current Perspective ◽  
Viral Components

Abstract Background In the past decades, researchers have demonstrated the critical role of Toll-like receptors (TLRs) in the innate immune system. They recognize viral components and trigger immune signal cascades to subsequently promote the activation of the immune system. Main body Herpesviridae family members trigger TLRs to elicit cytokines in the process of infection to activate antiviral innate immune responses in host cells. This review aims to clarify the role of TLRs in the innate immunity defense against herpesviridae, and systematically describes the processes of TLR actions and herpesviridae recognition as well as the signal transduction pathways involved. Conclusions Future studies of the interactions between TLRs and herpesviridae infections, especially the subsequent signaling pathways, will not only contribute to the planning of effective antiviral therapies but also provide new molecular targets for the development of antiviral drugs.

A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 77-77
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Yiming Huang ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Critical Role ◽  
Innate Immune ◽  
Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

scholarly journals Bioactive Nutrients and Nutrigenomics in Age-Related Diseases

2016 ◽  
Author(s):  
Tania Rescigno ◽  
Mario F. Tecce ◽  
Anna Capasso
Keyword(s):  
Oxidative Stress ◽  
Immune System ◽  
Aging Process ◽  
Bioactive Molecules ◽  
Low Grade ◽  
Molecular Processes ◽  
Ample Evidence ◽  
Inflammatory Status ◽  
Age Related

The increase in the average lifespan and the consequent proportional growth of the elderly segment of society has furthered the interest in studying ageing processes. Ageing may be considered a multifactorial process derived from the interaction between genetic and environmental factors including lifestyle. There is ample evidence in many species that the maximum age attainable (maximum lifespan potential, MLSP) is genetically determined and several mitochondrial DNA polymorphisms are associated with longevity. Many studies have shown that most of the phenotypic characteristics observed in the aging process are the result of the occurrence, with age, of a low grade chronic pro-inflammatory status called "inflammaging", partially under genetic control. The term indicate that aging is accompanied by a low degree of chronic inflammatory, an up-regulation of inflammatory response and that inflammatory changes are common to many age-related diseases. Therefore, the theory of oxidation-inflammation was proposed as the main cause of aging. Accordingly, the chronic oxidative stress, that appears with age, affects all cells and especially those of the regulatory systems, such as the nervous, endocrine, and immune systems and the communication between them. This prevents an adequate homeostasis and, therefore, the preservation of health. It was also proposed that the immune system plays a key role in the aging process, specifically in the rate of aging, since there is a relationship between the redox state and functional capacity of immune cells and longevity of individuals. Moreover, the role of the immune system in senescence could be of universal application. A confirmation of the central role of the immune system in oxi-inflamm-aging is that the administrationintake? of adequate amounts of antioxidants in the diet improves immune function, decreases their oxidative stress, and consequently increases longevity. The promotion of healthy lifestyles is one of the major goals of governments and international agencies all over the world. Human molecular processes are influenced by both physiological pathways and exogenous factors which include, for instance, those originating from diet. Dietary intake has substantive effects on molecular processes of metabolic health. Nutrients can directly regulate physiological changes in human body. In fact, in addition to have an energetic and structural value, nutritional intake provides bioactive molecules which are selectively able to modulate specific metabolic pathways, noticeably affecting cardiovascular and neoplastic diseases development or progress. Numerous bioactive nutrients are being progressively identified and their chemopreventive effects are being described at clinical and molecular mechanism levels. Systematic analyses comprise all &ldquo;omics&rdquo; technologies (such as transcriptomics, proteomics and metabolomics) and the goal is to investigate bioactive molecules effects derived from the diet. Nutrigenomic knowledge on physiologic status and disease risk will provide both developments of better diagnostic procedures and of new therapeutic strategies specifically targeted on nutritionally relevant processes. The present review was aimed to understand the molecular mechanisms underlying beneficial effects of bioactive nutrients and nutrigenomics on age-related diseases.

scholarly journals β-Glucan and parasites

2018 ◽  
Vol 55 (3) ◽  
pp. 177-184 ◽  
Author(s):  
V. Vetvicka ◽  
R. Fernandez-Botran
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Immune System ◽  
Parasitic Infections ◽  
Specific Immunity

Summary Immunosuppression caused by parasitic infections represents the foremost way by which the parasites overcome or escape the host’s immune response. Glucan is a well-established natural immunomodulator with the ability to significantly improve immune system, from innate immunity to both branches of specific immunity. Our review is focused on the possible role of glucan’s action in antiparasite therapies and vaccine strategies. We concluded that the established action of glucan opens a new window in treatment and protection against parasitic infections.

scholarly journals Mechanisms of innate immunity in pathogenesis of psoriasis: approaches to targeted therapy

2020 ◽  
Vol 22 (3) ◽  
pp. 449-458
Author(s):  
E. D. Merkushova ◽  
E. M. Khasanova ◽  
L. V. Gankovskaya
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Targeted Therapy ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pathological Process ◽  
Climatic Conditions ◽  
Keratinocyte Differentiation

Psoriasis is a chronic auto-inflammatory, genetically determined dermatosis, being multifactorial by origin, characterized by hyperproliferation of epidermis, affected keratinocyte differentiation and inflammatory reaction in dermis. The disease is characterized by a tendency to spread over the area of lesion, and involvement of articular tissue in the pathological process, which significantly affects the living standards of patients and causes their disability. There are many provoking factors that contribute to occurrence of psoriasis, or progression of existing psoriatic process in individuals with a genetic predisposition. These factors include adverse climatic conditions, skin trauma, exposure to ultraviolet light, burns, infections, etc.This review describes the role of innate immunity in pathogenesis of psoriasis, and describes in detail the mechanisms involved into induction of inflammation of PAMPs and DAMPs. In psoriasis, positively charged catelicidin is considered one of the most important DAMPs, which can form a complex with negatively charged cell polyanions-LL-37/auto-RNA and LL-37/auto-DNA. The interaction of PAMP/DAMP ligands with specific PRR receptors leads to signal activation of effector components of immune system, i.e., assembly of inflammasome complex, caspase activation, synthesis of inflammatory cytokines and processing of their immature forms. The review focuses on the role of TLRs under the conditions of physiological norm, which recognize danger signals and provide protection from pathogens and their timely elimination, and in development of pathological process. Activation of TLRs induces the production of pro-inflammatory cytokines, interferons and antimicrobial peptides, chemokines that support the development of psoriatic inflammation.In addition to TLRs, the mechanisms of involvement of inflammasomes in the development of psoriasis, which provides processing of mature forms of IL-1β and IL-18, are described in detail. Mature forms of these cytokines mediate the development of inflammation in psoriatic focus. In addition, processing of these cytokines by caspases using the positive feedback mechanism provides an additional signal to activate transcriptional activity of their genes and contributes to perpetuated inflammation.The review presents data confirming participation of inflammasomes in the pathogenesis of psoriasis. Much attention is paid to description of pharmacological inhibitors of inflammasomes, which in the future may be the drugs of choice for treatment of inflammatory diseases. The study of molecular mechanisms of the innate immune system will reveal new approaches to prognosis and development of targeted therapy for psoriasis.

scholarly journals Allergen-associated molecular patterns: a new trend in modern allergology

2019 ◽  
Vol 18 (1) ◽  
pp. 76-83
Author(s):  
V. S. Sviridova ◽  
P. Yu. Isaev ◽  
V. V. Klimov ◽  
M. I. Romanova ◽  
N. S. Koshkarova
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Adaptive Immune System ◽  
Conserved Motifs ◽  
Immune Mechanisms ◽  
Adaptive Immune ◽  
Molecular Patterns

Over the last decade the role of innate immunity has been known to be crucial for the activation of adaptive immune system. The main triggers that upregulate reactions of innate immunity are small exogenous molecules with conserved motifs, molecular patterns. The article discusses a variety of possible roles of molecular patterns in the immune mechanisms, including the participation of Allergen Associated Molecular Patterns (AAMPs) in allergic processes.

scholarly journals Mismatch in Sirpα, a Regulatory Protein in Innate Immunity, Is Associated with Outcomes of Allogeneic Stem Cell Transplantation for Lymphoid Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1804-1804
Author(s):  
Rima M. Saliba ◽  
Uri Greenbaum ◽  
Qing Ma ◽  
Samer A. Srour ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Stem Cell ◽  
Immune System ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Regulatory Protein ◽  
Innate Immune ◽  
Lymphoid Malignancies ◽  
Related Donor

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with hematologic malignancies. It is conventionally believed that alloreactivity is initiated by T-cells recognizing the non-self HLA molecules on the graft. Cells from the innate immune system, such as macrophages and monocytes, are induced by nonspecific "danger" molecules released from damaged tissue. Recent studies revealed that the innate immune system could distinguish the non-self graft and subsequently prime the adaptive immune system to advance the allorecognition process. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on macrophages and myeloid cells. The interaction between SIRPα and its ubiquitously expressed ligand, CD47, suppresses the macrophages phagocytic function. It has been demonstrated that recipient's monocytes detect polymorphism in SIRPα, and mismatches of SIRPα between donor and recipient can regulate the allorecognition response in the murine model. Our group has recently investigated the role of SIRPα variant mismatch in recipients of allo-HSCT from an HLA-matched related donor for treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We found that donor/recipient SIRPα mismatch was commonly detected in 39% of transplant pairs, and the presence of the mismatch was significantly associated with an increase rate of chronic graft-versus-host disease (cGvHD) and a lower rate of early relapse. We hypothesized that comparable effects could be occurring in recipients of allo-HSCT for treatment of lymphoid malignancies. We tested our hypothesis in a cohort of patients who received an allo-HSCT from an HLA matched-related donor at our institution between January 2008 and December 2018 for the treatment of lymphoid malignancies. Only patients who received a peripheral blood stem cell graft and tacrolimus/methotrexate for GvHD prophylaxis were eligible for the study. A total of 313 patients met the eligibility criteria including 310 (99%) who engrafted and 3 (1%) who died early before engraftment. The risk of early death was not associated with SIRPα mismatch variant. Only patients who engrafted (N=310) were included in subsequent analyses. Among these, 42% (N=130) of donor/recipient pairs were SIRPα mismatched. The majority of patients were treated for acute lymphoblastic leukemia (N=115, 37%) or non-Hodgkin's lymphoma (NHL) (N=114, 37%), followed by chronic lymphoblastic leukemia (N=59, 19%), and Hodgkin's lymphoma (N=22, 7%). Most (N=259, 84%) of patients had chemo-sensitive disease. The median age at transplant was 51 (range: 18-72) years, and 64% of patients were female. The median age of donors was 50 (range: 18-79) years and 53% were male. Conditioning regimens were myeloablative in 52% of cases. Outcomes were evaluated accounting for competing risks. The median follow-up in surviving patients was 74 (range: 3-124) months. A total of 99, 84, 108, and 51 patients experienced grade 2-4 acute GvHD, cGvHD requiring systemic immunosuppressive therapy, disease progression, and non-relapse mortality (NRM), respectively. Multivariate analyses showed that SIRPα mismatch was associated with a significantly higher rate (hazard ratio [HR]=1.9, P=.005) of cGvHD requiring systemic immunosuppressive therapy, and a lower rate (HR=.5, P=.004) of disease progression. Notably, the increased rate of cGVHD was consistent across the 4 lymphoid malignancies evaluated, yet the lower rate of relapse was observed in all diagnoses except NHL. There was no significant impact of SIRPα mismatch on grade 2-4 acute GvHD (HR=1.2, P=.3) or on NRM (HR=0.7, P=.3). Consistent with our preceding study in the AML/MDS cohort, the mismatch in SIRPα, a regulatory protein in innate immunity, is associated with a higher rate of cGvHD and relapse protection in patients who underwent allo-HSCT for lymphoid malignancies. The results of this study could be clinically important in donor selection and provide insight into the underlying role of innate immunity in allo-HSCT. Disclosures Shpall: Adaptimmune: Consultancy; Takeda: Patents & Royalties; Novartis: Consultancy; Magenta: Honoraria; Navan: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Magenta: Consultancy; Axio: Consultancy; Affimed: Patents & Royalties; Novartis: Honoraria.

scholarly journals Loss of microbiota depletes cross-reactive Foxp3+ Tregs leading to selective immunopathologies

2017 ◽  
Author(s):  
Tirumalai Kamala ◽  
David Usharauli
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Predictive Power ◽  
Hygiene Hypothesis ◽  
Immune Disorders ◽  
Evolutionary Time ◽  
Specific Nature ◽  
Vaccine Responses ◽  
Commensal Microbiota

The 'Hygiene hypothesis', a cornerstone model to account for the role of exogenous pathogens and later of endogenous microbiota in immune disorders, is currently presumed to operate at the innate immunity and metabolite levels to properly 'educate' the immune system. Doing so however fails to satisfactorily account for the antigen-specific nature of such disorders. SPIRAL is a novel interpretive framework that resolves this dilemma. It represents the periodic table of cross-reactive Foxp3+ regulatory T cell (Treg) epitopes selected from commensal microbiota over evolutionary time to mediate self-nonself discrimination and effector class regulation. Here, we utilize the SPIRAL's predictive power to provide a mechanistic antigen-specific basis for the initiation of allergies and autoimmune diseases as well as for the failure to mount effective anti-tumor and vaccine responses through selective loss of microbiota and corresponding cross-reactive Foxp3+ Tregs.

scholarly journals Innate Immunity to Spiral Ganglion Neuron Loss: A Neuroprotective Role of Fractalkine Signaling in Injured Cochlea

2021 ◽  
Vol 15 ◽  
Author(s):  
Andrew Rigel Stothert ◽  
Tejbeer Kaur
Keyword(s):  
Innate Immunity ◽  
Nervous System ◽  
Immune System ◽  
Inner Ear ◽  
Immune Cells ◽  
Spiral Ganglion ◽  
Sensory Cells ◽  
Specific Chemical ◽  
Ganglion Neurons

Immune system dysregulation is increasingly being attributed to the development of a multitude of neurodegenerative diseases. This, in large part, is due to the delicate relationship that exists between neurons in the central nervous system (CNS) and peripheral nervous system (PNS), and the resident immune cells that aid in homeostasis and immune surveillance within a tissue. Classically, the inner ear was thought to be immune privileged due to the presence of a blood-labyrinth barrier. However, it is now well-established that both vestibular and auditory end organs in the inner ear contain a resident (local) population of macrophages which are the phagocytic cells of the innate-immune system. Upon cochlear sterile injury or infection, there is robust activation of these resident macrophages and a predominant increase in the numbers of macrophages as well as other types of leukocytes. Despite this, the source, nature, fate, and functions of these immune cells during cochlear physiology and pathology remains unclear. Migration of local macrophages and infiltration of bone-marrow-derived peripheral blood macrophages into the damaged cochlea occur through various signaling cascades, mediated by the release of specific chemical signals from damaged sensory and non-sensory cells of the cochlea. One such signaling pathway is CX3CL1-CX3CR1, or fractalkine (FKN) signaling, a direct line of communication between macrophages and sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) of the cochlea. Despite the known importance of this neuron-immune axis in CNS function and pathology, until recently it was not clear whether this signaling axis played a role in macrophage chemotaxis and SGN survival following cochlear injury. In this review, we will explore the importance of innate immunity in neurodegenerative disease development, specifically focusing on the regulation of the CX3CL1-CX3CR1 axis, and present evidence for a role of FKN signaling in cochlear neuroprotection.

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