scholarly journals A novel role for CCR3 in brain T-cell infiltration and cognition in aging

2021 ◽  
Author(s):  
Arnaud Teichert ◽  
Sanket Rege ◽  
Juliet Masumi ◽  
Lily Akrapongpisak ◽  
Hannah Hackbart ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Direct Action ◽  
T Cell Infiltration ◽  
Age Related ◽  
Immune Mediated ◽  
Cognitive Benefits ◽  
Peripheral Immune Cells

Abstract Targeting immune-mediated, age-related, biology has the potential to be a transformative therapeutic strategy. However, the redundant nature of the multiple cytokines that change with aging requires identification of a master downstream regulator to successfully exert therapeutic efficacy. Here, we discovered CCR3 as a prime candidate, and inhibition of CCR3 has profound pro-cognitive benefits, but these benefits are not driven by an obvious direct action on CNS-resident cells. Instead, CCR3-expressing cells in the periphery that are modulated in aging inhibit infiltration of T cells across the blood-brain barrier and reduce neuroinflammation. The axis of CCR3-expressing peripheral immune cells influencing crosstalk from periphery to brain provides a novel and therapeutically tractable link. These findings indicate the broad therapeutic potential of CCR3 inhibition in a spectrum of neuroinflammatory diseases of aging.

scholarly journals Antipsoriatic Effects of Wannachawee Recipe on Imiquimod-Induced Psoriasis-Like Dermatitis in BALB/c Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Mingkwan Na Takuathung ◽  
Ariyaphong Wongnoppavich ◽  
Ampai Panthong ◽  
Parirat Khonsung ◽  
Natthakarn Chiranthanut ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Dorsal Skin ◽  
Inflammatory Skin Disease ◽  
Epidermal Thickness ◽  
Oral Gavage ◽  
T Cell Infiltration ◽  
Immune Mediated ◽  
Th17 Cytokines ◽  
Potential Alternative

Psoriasis is a common immune-mediated chronic inflammatory skin disease characterized by thick and erythema raised plaques with adherent silvery scales. T-cells are activated via the IL-23/Th17 axis which is involved in psoriasis pathogenesis. Conventional treatments of psoriasis have adverse events that influence patients’ adherence. Wannachawee Recipe (WCR) is Thai traditional medicine that is known to be effective for psoriasis patients; however, preclinical evidence is still lacking. This study investigated the therapeutic potential of WCR on antiproliferant activity using imiquimod- (IMQ-) induced psoriasis-like dermatitis in a mouse model. Psoriasis-like dermatitis was induced on the shaved dorsal skin and right ear pinna of BALB/c mice by topical application of IMQ for 15 consecutive days after which WCR was administered to the mice by oral gavage for 10 days. Phenotypical observations, histopathological examinations, and ELISA of skin and blood samples were conducted. WCR significantly ameliorated development of IMQ-induced psoriasis-like dermatitis and reduced levels of Th17 cytokines (IL-17A, IL-22, and IL-23) in both serum and dorsal skin. Histopathological findings showed a decrease in epidermal thickness and inflammatory T-cell infiltration in the WCR-treated groups. The WCR has pharmacological actions which regulate Th17 related cytokines suggesting that it is a potential alternative therapeutic strategy for psoriasis.

scholarly journals Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

2021 ◽  
Vol 7 (21) ◽  
pp. eabe4601
Author(s):  
Sandro Da Mesquita ◽  
Jasmin Herz ◽  
Morgan Wall ◽  
Taitea Dykstra ◽  
Kalil Alves de Lima ◽  
...  
Keyword(s):  
T Cells ◽  
Cognitive Decline ◽  
Brain Aging ◽  
Therapeutic Potential ◽  
T Cell Response ◽  
Age Related ◽  
Lymphatic Vasculature ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

The Intersection of Metformin and Inflammation

2021 ◽  
Author(s):  
Leena P. Bharath ◽  
Barbara S. Nikolajczyk
Keyword(s):  
Mitochondrial Function ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Remarkable Effect ◽  
Tumor Onset ◽  
Age Related ◽  
Immune Mediated ◽  
Autoimmune Conditions ◽  
Near Term

The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug. Commonly accepted mechanisms of metformin action include AMPK activation and inhibition of mTOR pathways, which are evaluated in multiple diseases. Additionally, metformin's action on mitochondrial function and cellular homeostasis processes such as autophagy, is of particular interest because of the importance of these mechanisms in maintaining cellular health. Both dysregulated mitochondria and failure of the autophagy pathways, the latter of which impair clearance of dysfunctional, damaged, or excess organelles, affect cellular health drastically and can trigger the onset of metabolic and age-related diseases. Immune cells are the fundamental cell types that govern the health of an organism. Thus, dysregulation of autophagy or mitochondrial function in immune cells has a remarkable effect on susceptibility to infections, response to vaccination, tumor onset, and the development of inflammatory and autoimmune conditions. Here we summarize the latest research on metformin's regulation of immune cell mitochondrial function and autophagy as evidence that new clinical trials on metformin with primary outcomes related to the immune system should be considered to treat immune-mediated diseases over the near term.

scholarly journals Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation

2022 ◽  
Vol 15 ◽  
Author(s):  
Nynke J. van den Hoogen ◽  
Erika K. Harding ◽  
Chloé E. D. Davidson ◽  
Tuan Trang
Keyword(s):  
Chronic Pain ◽  
Immune Cells ◽  
Therapeutic Potential ◽  
Emotional Experience ◽  
Opioid Analgesics ◽  
Pain Modulation ◽  
Pain Outcomes ◽  
Cb2 Receptors ◽  
Affective Components ◽  
Peripheral Immune Cells

Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

scholarly journals The Complex Role of Regulatory T Cells in Immunity and Aging

2021 ◽  
Vol 11 ◽  
Author(s):  
Lourdes Rocamora-Reverte ◽  
Franz Leonard Melzer ◽  
Reinhard Würzner ◽  
Birgit Weinberger
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Immune Cells ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Γδt Cells ◽  
Cell Functions ◽  
Age Related ◽  
Self Antigens

The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4+ T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8+ T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.

scholarly journals The Complexity of Microglial Interactions With Innate and Adaptive Immune Cells in Alzheimer’s Disease

2020 ◽  
Vol 12 ◽  
Author(s):  
Season K. Wyatt-Johnson ◽  
Randy R. Brutkiewicz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Immune Cells ◽  
Reactive Microglia ◽  
Adaptive Immune Cells ◽  
Affected Relative ◽  
Peripheral Immune Cells

In the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.

scholarly journals Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amin Ahmadi ◽  
Reza Moghadasali ◽  
Vahid Ezzatizadeh ◽  
Zeinab Taghizadeh ◽  
Seyed Mahdi Nassiri ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Membranous Nephropathy ◽  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Induced Pluripotent Stem Cell ◽  
Glomerular Diseases ◽  
Heavy Proteinuria ◽  
Immune Mediated ◽  
Induced Pluripotent ◽  
Shed Light

Abstract Injury to podocytes is a principle cause of initiation and progression of both immune and non-immune mediated glomerular diseases that result in proteinuria and decreased function of the kidney. Current advances in regenerative medicine shed light on the therapeutic potential of cell-based strategies for treatment of such disorders. Thus, there is hope that generation and transplantation of podocytes from induced pluripotent stem cells (iPSCs), could potentially be used as a curative treatment for glomerulonephritis caused by podocytes injury and loss. Despite several reports on the generation of iPSC-derived podocytes, there are rare reports about successful use of these cells in animal models. In this study, we first generated a model of anti-podocyte antibody-induced heavy proteinuria that resembled human membranous nephropathy and was characterized by the presence of sub-epithelial immune deposits and podocytes loss. Thereafter, we showed that transplantation of functional iPSC-derived podocytes following podocytes depletion results in recruitment of iPSC-derived podocytes within the damaged glomerulus, and leads to attenuation of proteinuria and histological alterations. These results provided evidence that application of iPSCs-derived renal cells could be a possible therapeutic strategy to favorably influence glomerular diseases outcomes.

scholarly journals RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

2014 ◽  
Vol 211 (5) ◽  
pp. 943-959 ◽  
Author(s):  
Yanping Xiao ◽  
Sanhong Yu ◽  
Baogong Zhu ◽  
Denis Bedoret ◽  
Xia Bu ◽  
...  
Keyword(s):  
T Cells ◽  
Bone Morphogenetic Proteins ◽  
Therapeutic Potential ◽  
Alveolar Epithelial Cells ◽  
Binding Partner ◽  
Alveolar Epithelial ◽  
Immune Mediated ◽  
Programmed Death ◽  
Repulsive Guidance Molecule ◽  
Guidance Molecule

We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb–PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2–deficient mice showed that PD-L2 expression on non–T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events.

scholarly journals Age-related sexual dimorphism on the longitudinal progression of blood immune cells in BALB/cByJ mice

2021 ◽  
Author(s):  
Cláudia Serre-Miranda ◽  
Susana Roque ◽  
Palmira Barreira-Silva ◽  
Claudia Nobrega ◽  
Neide Vieira ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Sexual Dimorphism ◽  
B Cells ◽  
Nk Cells ◽  
Mouse Models ◽  
Immune Cells ◽  
Age Related ◽  
The Impact ◽  
Over Time

Abstract The study of immune system aging is of relevance, considering its myriad of interactions and role in protecting and maintaining body homeostasis. While mouse models have been extensively used to study immune system aging, little is known on how the main immune populations progress over time and what is the impact of sex. To contribute to filling this gap, male and female BALB/cByJ mice were longitudinally evaluated, from 3 to 18 months old, for the main blood populations, assessed by flow cytometry. Using linear mixed-effect models, we observed that the percentages of neutrophils, monocytes, eosinophils and total natural killer (NK) cells increase with aging; while those of B cells, T cells (including CD4 + and CD8 + subsets) and Ly6C + NK cells, decrease. Males present higher percentages of neutrophils and classical monocytes Ly6C high over time, while females present higher percentages of total T cells, both CD4 + and CD8 +, eosinophils and NK cells. Males and females display similar percentages of B cells, even though with opposite accelerated progressions over time. This study revealed that mouse models recapitulate what is observed in humans during aging: an overall proportional decrease in the adaptive and an increase in the innate immune cells. Additionally, it uncovers an age-related sexual dimorphism in the proportion of immune cells in circulation, further strengthening the need to explore the impact of sex when addressing immune system aging using mouse models.

scholarly journals Probiotics Improve Autoimmune Hepatitis via Gut Mycobiota-Mediated Follicular Helper T Cells

2021 ◽  
Author(s):  
Liang Ma ◽  
Liwen Zhang ◽  
Yun Zhuang ◽  
Yanbo Ding ◽  
Jianping Chen
Keyword(s):  
T Cells ◽  
Autoimmune Hepatitis ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Real Time Quantitative Pcr ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Immune Mediated

Abstract Background: Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver dysfunction. The follicular helper (TFH) T cells play critical roles in the immunopathogenesis and progression of AIH. But the underlying mechanism of the dysregulation of TFH cells in AIH remains to be determined. Therefore, we aimed to investigate the effect of gut mycobiota on TFH cell response in AIH. Methods: Samples from AIH patients and the EAH animal model were analyzed using Real-time quantitative PCR (RT-qPCR), Enzyme-linked immunosorbent assay (ELISA), western blotting, flow cytometry, and Hematoxylin-eosin (HE) staining to determine the role of gut mycobiota on autoimmune hepatitis.Results: Lactobacillus capsule could significantly increased the levels of Bacteroides fragilis, Clostridium, Clostridium leptum, Bifi, and Lacto in AIH patients and significantly decreased the levels of ALT, AST, TBIL, SMA, ANA, DAO, and ET in AIH patients. What’s more, the Lactobacillus capsule showed similar results in EAH mice. it decreased the levels of serum IL-21, the proportions of TFH cells in CD4+ T cells as well as TFH related cytokines and factors. Mechanistically, lactobacillus capsule regulated TFH response in EAH mice in DCs and MyD88/NF-κB pathway-dependent manner. Conclusion: Our results suggested a protective and therapeutic potential of probiotics in the treatment of AIH.

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