scholarly journals Deficiency of p38α-MAPK in myeloid cells ameliorates symptoms and pathology of APP-transgenic Alzheimer's disease mice

2021 ◽  
Author(s):  
Qinghua Luo ◽  
Laura Schnöder ◽  
Wenlin Hao ◽  
Kathrin Litzenburger ◽  
Yann Decker ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Microglial Activation ◽  
Cell Lineage ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Inflammatory Activation ◽  
P38α Mapk ◽  
Novel Target ◽  
The Brain ◽  
Ad Therapy

Microglial activation is a hall marker of Alzheimer disease (AD); its pathogenic role and regulating mechanisms are unclear. In APP-transgenic mice, we deleted p38α-MAPK in the myeloid cell lineage from birth or specifically in microglia from 9 months, and analysed the AD pathology at the age of 4, 9 and 12 months. In both experimental settings, p38α-MAPK deficiency decreased cerebral Aβ and improved cognitive function in AD mice; however, p38α-MAPK deficiency in whole myeloid cells was more effective than specifically in microglia in preventing AD pathogenesis. Deficiency of p38α-MAPK in whole myeloid cells inhibited the inflammatory activation of individual microglia by 4 months, but enhanced it by 9 months. Inflammatory activation was essential for p38α-MAPK deficiency to promote microglial internalization of Aβ in the brain. In the investigation of mechanisms mediating different effects of p38α-MAPK-deficient myeloid cells and p38α-MAPK-deficient microglia on the pathogenesis of AD mice, we observed that p38α-MAPK deficiency in peripheral myeloid cells reduced il-17a transcription in CD4-positive spleen cells. By cross-breeding APP-transgenic mice and IL-17a knockout mice, we further found that IL-17a deficiency activated microglia and decreased Aβ deposits in AD mouse brain. In summary, our study shows that p38α-MAPK deficiency in myeloid cells attenuates symptoms and pathology of APP-transgenic mice. As a potential mechanism, p38α-MAPK-deficient peripheral myeloid cells reduces IL-17a-expressing T lymphocytes, and subsequently regulates cerebral Aβ clearance in APP-transgenic mice. Together with our previous observations that a deficiency of p38α-MAPK in neurons prevents AD pathogenesis, our study supports p38α-MAPK as a novel target for AD therapy.

scholarly journals Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke

2018 ◽  
Vol 39 (10) ◽  
pp. 1906-1918 ◽  
Author(s):  
Kota Kurisu ◽  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Jian Shi ◽  
Atsushi Kanoke ◽  
...  
Keyword(s):  
Cell Activation ◽  
Infarct Volume ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cerebrovascular Diseases ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Neurological Outcomes ◽  
Intact Brain ◽  
The Brain

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.

scholarly journals Immune System in the Brain: A Modulatory Role on Dendritic Spine Morphophysiology?

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Oscar Kurt Bitzer-Quintero ◽  
Ignacio González-Burgos
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune System ◽  
Dendritic Spines ◽  
Cell Lineage ◽  
Myeloid Cell ◽  
Brain Parenchyma ◽  
Immune Mediators ◽  
The Central Nervous System ◽  
The Brain

The central nervous system is closely linked to the immune system at several levels. The brain parenchyma is separated from the periphery by the blood brain barrier, which under normal conditions prevents the entry of mediators such as activated leukocytes, antibodies, complement factors, and cytokines. The myeloid cell lineage plays a crucial role in the development of immune responses at the central level, and it comprises two main subtypes: (1) resident microglia, distributed throughout the brain parenchyma; (2) perivascular macrophages located in the brain capillaries of the basal lamina and the choroid plexus. In addition, astrocytes, oligodendrocytes, endothelial cells, and, to a lesser extent, neurons are implicated in the immune response in the central nervous system. By modulating synaptogenesis, microglia are most specifically involved in restoring neuronal connectivity following injury. These cells release immune mediators, such as cytokines, that modulate synaptic transmission and that alter the morphology of dendritic spines during the inflammatory process following injury. Thus, the expression and release of immune mediators in the brain parenchyma are closely linked to plastic morphophysiological changes in neuronal dendritic spines. Based on these observations, it has been proposed that these immune mediators are also implicated in learning and memory processes.

scholarly journals Circulating myeloid cells invade the central nervous system to mediate cachexia during pancreatic cancer

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kevin G Burfeind ◽  
Xinxia Zhu ◽  
Mason A Norgard ◽  
Peter R Levasseur ◽  
Christian Huisman ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Purinergic Receptor ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Ductal Adenocarcinoma ◽  
The Central Nervous System ◽  
Velum Interpositum ◽  
The Brain

Weight loss and anorexia are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. Pharmacologic CCR2 blockade and genetic deletion of Ccr2 both resulted in significantly decreased brain-infiltrating myeloid cells as well as attenuated cachexia during PDAC. Lastly, intracerebroventricular blockade of the purinergic receptor P2RX7 during PDAC abolished immune cell recruitment to the brain and attenuated anorexia. Our data demonstrate a novel function for the CCR2/CCL2 axis in recruiting neutrophils to the brain, which drives anorexia and muscle catabolism.

scholarly journals Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lindsay A Hohsfield ◽  
Allison R Najafi ◽  
Yasamine Ghorbanian ◽  
Neelakshi Soni ◽  
Joshua Crapser ◽  
...  
Keyword(s):  
White Matter ◽  
Subventricular Zone ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Distinct Pattern ◽  
Adult Brain ◽  
The Brain ◽  
Stimulating Factor ◽  
Insight Into ◽  
Dynamic Wave

Microglia, the brain’s resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas. Following CSF1Ri, these amoeboid cells migrate radially and tangentially in a dynamic wave filling the brain in a distinct pattern, to replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit similar phenotypic and transcriptional profiles to white-matter-associated microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into repopulating microglia function and dynamics in the mouse brain.

scholarly journals Pinpointing Brain TREM2 Levels in Two Mouse Models of Alzheimer’s Disease

2021 ◽  
Author(s):  
Silvio R. Meier ◽  
Dag Sehlin ◽  
Greta Hultqvist ◽  
Stina Syvänen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Microglial Activation ◽  
Bispecific Antibody ◽  
Ex Vivo ◽  
Transgenic Animals ◽  
The Brain

Abstract Purpose The triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by brain microglia. Microglial activation, as observed in Alzheimer’s disease (AD) as well as in transgenic mice expressing human amyloid-beta, appears to increase soluble TREM2 (sTREM2) levels in CSF and brain. In this study, we used two different transgenic mouse models of AD pathology and investigated the potential of TREM2 to serve as an in vivo biomarker for microglial activation in AD. Procedures We designed and generated a bispecific antibody based on the TREM2-specific monoclonal antibody mAb1729, fused to a single-chain variable fragment of the transferrin receptor binding antibody 8D3. The 8D3-moiety enabled transcytosis of the whole bispecific antibody across the blood-brain barrier. The bispecific antibody was radiolabeled with I-125 (ex vivo) or I-124 (PET) and administered to transgenic AD and wild-type (WT) control mice. Radioligand retention in the brain of transgenic animals was compared to WT mice by isolation of brain tissue at 24 h or 72 h, or with in vivo PET at 24 h, 48 h, and 72 h. Intrabrain distribution of radiolabeled mAb1729-scFv8D3CL was further studied by autoradiography, while ELISA was used to determine TREM2 brain concentrations. Results Transgenic animals displayed higher total exposure, calculated as the AUC based on SUV determined at 24h, 48h, and 72h post injection, of PET radioligand [124I]mAb1729-scFv8D3CL than WT mice. However, differences were not evident in single time point PET images or SUVs. Ex vivo autoradiography confirmed higher radioligand concentrations in cortex and thalamus in transgenic mice compared to WT, and TREM2 levels in brain homogenates were considerably higher in transgenic mice compared to WT. Conclusion Antibody-based radioligands, engineered to enter the brain, may serve as PET radioligands to follow changes of TREM2 in vivo, but antibody formats with faster systemic clearance to increase the specific signal in relation to that from blood in combination with antibodies showing higher affinity for TREM2 must be developed to further progress this technique for in vivo use.

scholarly journals Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice

2015 ◽  
Vol 212 (11) ◽  
pp. 1811-1818 ◽  
Author(s):  
Stefan Prokop ◽  
Kelly R. Miller ◽  
Natalia Drost ◽  
Susann Handrick ◽  
Vidhu Mathur ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Myeloid Cell ◽  
Amyloid Plaques ◽  
Full Potential ◽  
Antibody Treatment ◽  
App Processing ◽  
The Brain

Although central nervous system–resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer’s disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell–based therapies for AD.

scholarly journals Aging-Associated Decrease in the Histone Acetyltransferase KAT6B Causes Myeloid-Biased Hematopoietic Stem Cell Differentiation

2019 ◽  
Author(s):  
Eraj Shafiq Khokhar ◽  
Sneha Borikar ◽  
Elizabeth Eudy ◽  
Tim Stearns ◽  
Kira Young ◽  
...  
Keyword(s):  
Immune Function ◽  
Histone Acetyltransferase ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Stem Cell Differentiation ◽  
Hematopoietic Stem ◽  
Protein Levels ◽  
Novel Target

SummaryAged hematopoietic stem cells (HSCs) undergo biased lineage priming and differentiation toward production of myeloid cells. A comprehensive understanding of gene regulatory mechanisms causing HSC aging is needed to devise new strategies to sustainably improve immune function in aged individuals. Here, a focused shRNA screen of epigenetic factors reveals that the histone acetyltransferase Kat6b regulates myeloid cell production from hematopoietic progenitor cells. Within the stem and progenitor cell compartment, Kat6b is most highly expressed in long-term (LT)-HSCs and is significantly decreased with aging at the transcript and protein levels. Knockdown of Kat6b in young LT-HSCs causes skewed production of myeloid cells both in vitro and in vivo. Transcriptome analysis identifies enrichment of aging and macrophage-associated gene signatures alongside reduced expression of self-renewal and multilineage priming signatures. Together, our work identifies KAT6B as an epigenetic regulator of LT-HSC aging and a novel target to improve aged immune function.

scholarly journals MERS-CoV infection causes brain damage in human DPP4-transgenic mice through complement-mediated inflammation

2021 ◽  
Vol 102 (10) ◽  
Author(s):  
Yuting Jiang ◽  
Yuehong Chen ◽  
Hong Sun ◽  
Xiaolu Zhang ◽  
Lei He ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Complement Activation ◽  
Peripheral Nerves ◽  
Microglial Activation ◽  
Inflammatory Cell ◽  
Adjunctive Treatment ◽  
Cns Injury ◽  
C5a Receptor ◽  
Highly Pathogenic ◽  
The Brain

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.

scholarly journals Distinct features of human myeloid cell cytokine response profiles identify neutrophil activation by cytokines as a prognostic feature during tuberculosis and cancer1

2019 ◽  
Author(s):  
Joseph C. Devlin ◽  
Erin E. Zwack ◽  
Mei San Tang ◽  
Zhi Li ◽  
David Fenyo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Lineage ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Specific Response ◽  
Transcriptional Responses ◽  
Prognostic Features ◽  
Cytokine Activation ◽  
Inflammatory Conditions ◽  
Ifn Γ

ABSTRACTMyeloid cells are a vital component of innate immunity and comprise of monocytes, macrophages, dendritic cells and granulocytes. How myeloid cell lineage affects activation states in response to cytokines remains poorly understood. The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils in response to stimulation by IFN-γ, IFN-β IFN-λ, IL-4, IL-13 and IL-10 cytokines, to better understand the heterogeneity of activation states in inflammatory conditions. This generated a myeloid cell cytokine specific response matrix that can infer representation of myeloid cells and the cytokine environment they encounter during infection and in tumors. Neutrophils were highly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-β stimulation, whereas other IFN signature genes were upregulated by both IFN-γ and IFN-β. When we used our matrix to deconvolute blood profiles from tuberculosis patients, the IFN-β specific neutrophil signature was reduced in TB patients with active disease whereas the shared response to IFN-γ and IFN-β in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-γ or IFN-β emerged as opposing predictors of patient survival. Hence, by dissecting how different myeloid cells respond to cytokine activation, we can delineate biological roles for myeloid cells in different cytokine environments during disease processes, especially during infection and tumor progression.

scholarly journals Implication and Regulation of AMPK during Physiological and Pathological Myeloid Differentiation

2018 ◽  
Vol 19 (10) ◽  
pp. 2991 ◽  
Author(s):  
Arnaud Jacquel ◽  
Frederic Luciano ◽  
Guillaume Robert ◽  
Patrick Auberger
Keyword(s):  
Protein Kinase ◽  
Mammalian Cells ◽  
Hematopoietic Cells ◽  
Cell Lineage ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Energy Status ◽  
Hematopoietic Stem ◽  
Myeloid Malignancies

AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase consisting of the arrangement of various α β, and γisoforms that are expressed differently depending on the tissue or the cell lineage. AMPK is one of the major sensors of energy status in mammalian cells and as such plays essential roles in the regulation of cellular homeostasis, metabolism, cell growth, differentiation, apoptosis, and autophagy. AMPK is activated by two upstream kinases, the tumor suppressor liver kinase B1 (LKB1) and the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) through phosphorylation of the kinase on Thr172, leading to its activation. In addition, AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. Although it is well established that AMPK can control the differentiation of different cell lineages, including hematopoietic stem cells (HSCs), progenitors, and mature hematopoietic cells, the role of AMPK regarding myeloid cell differentiation is less documented. The differentiation of monocytes into macrophages triggered by colony stimulating factor 1 (CSF-1), a process during which both caspase activation (independently of apoptosis induction) and AMPK-dependent stimulation of autophagy are necessary, is one noticeable example of the involvement of AMPK in the physiological differentiation of myeloid cells. The present review focuses on the role of AMPK in the regulation of the physiological and pathological differentiation of myeloid cells. The mechanisms of autophagy induction by AMPK will also be addressed, as autophagy has been shown to be important for differentiation of hematopoietic cells. In addition, myeloid malignancies (myeloid leukemia or dysplasia) are characterized by profound defects in the establishment of proper differentiation programs. Reinduction of a normal differentiation process in myeloid malignancies has thus emerged as a valuable and promising therapeutic strategy. As AMPK seems to exert a key role in the differentiation of myeloid cells, notably through induction of autophagy, we will also discuss the potential to target this pathway as a pro-differentiating and anti-leukemic strategy in myeloid malignancies.

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