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 Krüppel like factor 2 - deficient myeloid cells promote skeletal muscle regeneration after injury

2018 ◽  
Author(s):  
Palanikumar Manoharan ◽  
Taejeong Song ◽  
Tatiana L Radzyukevich ◽  
Sakthivel Sadayappan ◽  
Jerry B Lingrel ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Cell Activation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Innate Immune ◽  
Skeletal Muscle Regeneration ◽  
Adult Skeletal Muscle ◽  
Complex Interactions ◽  
Elevated Expression

Regeneration of adult skeletal muscle after injury is coordinated by complex interactions between the injured muscle and the innate immune system. Myeloid lineage cells predominate in this process. This study examined the role of Krüppel like factor 2 (KLF2), a zinc-finger transcription factor that regulates myeloid cell activation state, in muscle regeneration. Gastrocnemius muscles of wild-type and myeKlf2-/- mice, which lack KLF2 in all myeloid cells, were subjected to cardiotoxin injury and followed for 21 days. Injured muscles of myeKlf2-/- contained more infiltrating, inflammatory Ly6C+ monocytes, with elevated expression of inflammatory mediators. Infiltrating monocytes matured earlier into pro-inflammatory macrophages with phenotype Ly6C+, CD11b+, F4/80+. Inflammation resolved earlier and progressed to myogenesis, marked by an earlier decline of Ly6C+ macrophages and their replacement with anti-inflammatory Ly6C- populations, in association with elevated expression of factors that resolve inflammation and promote myogenesis. Overall, regeneration was completed earlier. These findings identify myeloid KLF2 as a central regulator of the innate immune response to acute skeletal muscle injury. Manipulating myeloid KLF2 levels may be a useful strategy for accelerating regeneration.

scholarly journals The Asparaginyl Endopeptidase Legumain after Experimental Stroke

2010 ◽  
Vol 30 (10) ◽  
pp. 1756-1766 ◽  
Author(s):  
Taku Ishizaki ◽  
Agnes Erickson ◽  
Enida Kuric ◽  
Mehrdad Shamloo ◽  
Ikuko Hara-Nishimura ◽  
...  
Keyword(s):  
Immune Cell ◽  
Infarct Volume ◽  
Recovery Period ◽  
Gene Array ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Post Stroke ◽  
Asparaginyl Endopeptidase ◽  
Infarct Area ◽  
Deficient Mice

Various proteases in the brain contribute to ischemic brain injury. We investigated the involvement of the asparaginyl endopeptidase legumain after experimental stroke. On the basis of gene array studies and in situ hybridizations, we observed an increase of legumain expression in the peri-infarct area of rats after transient occlusion of the middle cerebral artery (MCAO) for 120 mins with a maximum expression at 24 and 48 h. Immunohistochemical analyses revealed the expression of legumain in Iba1+ microglial cells and glial fibrillary acidic protein-positive astrocytes of the peri-infarct area in mice after MCAO. Post-stroke recovery was also studied in aged legumain-deficient mice (45 to 58 weeks old). Legumain-deficient mice did not show any differences in physiologic parameters compared with respective littermates before, during MCAO (45 mins), and the subsequent recovery period of 8 days. Moreover, legumain deficiency had no effect on mortality, infarct volume, and the neurologic deficit determined by the rotating pole test, a standardized grip strength test, and the pole test. However, a reduced number of invading CD74+ cells in the ischemic hemisphere indicates an involvement in post-stroke inflammation. We conclude that legumain is not essential for the functional deficit after MCAO but may be involved in mechanisms of immune cell invasion.

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 Intra-Arterial Stem Cell Transplantation in Experimental Stroke in Rats: Real-Time MR Visualization of Transplanted Cells Starting With Their First Pass Through the Brain With Regard to the Therapeutic Action

2021 ◽  
Vol 15 ◽  
Author(s):  
Daria D. Namestnikova ◽  
Ilya L. Gubskiy ◽  
Veronica A. Revkova ◽  
Kirill K. Sukhinich ◽  
Pavel A. Melnikov ◽  
...  
Keyword(s):  
Real Time ◽  
Close Contact ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Therapeutic Effects ◽  
Stroke Treatment ◽  
First Pass ◽  
Pass Through ◽  
The Brain

Cell therapy is an emerging approach to stroke treatment with a potential to limit brain damage and enhance its restoration after the acute phase of the disease. In this study we tested directly reprogrammed neural precursor cells (drNPC) derived from adult human bone marrow cells in the rat middle cerebral artery occlusion (MCAO) model of acute ischemic stroke using human placenta mesenchymal stem cells (pMSC) as a positive control with previously confirmed efficacy. Cells were infused into the ipsilateral (right) internal carotid artery of male Wistar rats 24 h after MCAO. The main goal of this work was to evaluate real-time distribution and subsequent homing of transplanted cells in the brain. This was achieved by performing intra-arterial infusion directly inside the MRI scanner and allowed transplanted cells tracing starting from their first pass through the brain vessels. Immediately after transplantation, cells were observed in the periphery of the infarct zone and in the brain stem, 15 min later small numbers of cells could be discovered deep in the infarct core and in the contralateral hemisphere, where drNPC were seen earlier and in greater numbers than pMSC. Transplanted cells in both groups could no longer be detected in the rat brain 48–72 h after infusion. Histological and histochemical analysis demonstrated that both the drNPC and pMSC were localized inside blood vessels in close contact with the vascular wall. No passage of labeled cells through the blood brain barrier was observed. Additionally, the therapeutic effects of drNPC and pMSC were compared. Both drNPC and pMSC induced substantial attenuation of neurological deficits evaluated at the 7th and 14th day after transplantation using the modified neurological severity score (mNSS). Some of the effects of drNPC and pMSC, such as the influence on the infarct volume and the survival rate of animals, differed. The results suggest a paracrine mechanism of the positive therapeutic effects of IA drNPC and pMSC infusion, potentially enhanced by the cell-cell interactions. Our data also indicate that the long-term homing of transplanted cells in the brain is not necessary for the brain’s functional recovery.

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 IMMU-34. LANDSCAPE OF GLIOBLASTOMA-ASSOCIATED IMMUNITY BY INTEGRATION OF scRNA-SEQ AND SPATIAL TRANSCRIPTOMICS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii112-ii112
Author(s):  
Vidhya Ravi ◽  
Nicolas Neidert ◽  
Kevin Joseph ◽  
Juergen Beck ◽  
Oliver Schnell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
T Cell Exhaustion ◽  
Cellular Interactions ◽  
Cell Exhaustion

Abstract The diversity of molecular states and cellular plasticity of immune cells within the glioblastoma (GBM) environment remain poorly investigated. Here, we conduct deep transcriptional profiling of lymphoid and myeloid cell populations by scRNA-sequencing, map potential cellular interactions and cytokine responses that lead to the dysfunctional and exhausted phenotype of T cells. We identified Interleukin 10 (IL-10) response during T cell activation, which lead to a dysfunctional state of T cells. By the use of a novel method: The nearest functionally connected neighbor (NFCN), an in-silico model to explore cell-cell interaction, the dysfunctional/exhausted phenotype was found to be driven by subset of myeloid cells defined by high expression of HMOX1. By using spatial transcriptomic RNA-sequencing, we identified a correlation between T cell exhaustion and colocalized mesenchymal gene expression. We found that HMOX1 expressing myeloid cells occupying regions marked by T cell exhaustion. Using a human neocortical slice model with myeloid cell depletion we confirmed the functional interaction of myeloid and lymphoid cell leading to the dysfunctional state of T cells. A comprehensive understanding of cellular states and plasticity of lymphoid cells in GBM aids in providing successful immunotherapeutic approaches.

scholarly journals VISTA Is a Novel Regulator of Macrophage Biology

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2320-2320
Author(s):  
Parth Shah ◽  
Mohamed Eltanbouly ◽  
Nicole Smits ◽  
Aurelien Sarde ◽  
Randolph Noelle ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Biology ◽  
Time Course ◽  
Cell Activation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Mouse Bone Marrow ◽  
Rna Seq

Background:V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint receptor with an established role as an inhibitory receptor on T cells. However, its role in myeloid cell biology remains unclear. Owing to the much higher expression of VISTA on monocytes and macrophages, we investigated its role in regulating myeloid biology. Methods: Mouse bone marrow-derived macrophages (BMDMs) were differentiated and treated with agonistic anti-VISTA mAb under steady-state and conditions of M1 inflammatory polarization (LPS + IFN-𝛾). Human CD14+ monocytes were isolated from peripheral blood and treated with anti-VISTA in vitro. Phosphoarrays were used to assess signaling downstream of VISTA engagement and Luminex analysis was used to evaluate cytokine production. Time-course total RNA-seq was performed on BMDMs (at 1, 2, 4, 8 and 16 hours of anti-VISTA treatment). To evaluate the effect of anti-VISTA in vivo, single-cell RNA-seq (scRNA-seq) was performed on FACS sorted CD11b+ myeloid populations 12 hours after mice were treated with intravenous anti-VISTA. Results: Anti-VISTA treatment of BMDMs and human monocytes in vitro induced rapid phosphorylation events including robust phosphorylation of Raf-1 kinase at the suppressive serine residue 43.Next, we generated a comprehensive timestamp of VISTA activation in BMDMs in vitro by time-course deep RNA-seq analysis of agonistic anti-VISTA treated cells under rigorous M1 inflammatory polarization. This revealed a unique activation state marked by the upregulation of inhibitory cytokines IL-10 and IL1RA as well as ablation of IL-12 family cytokines, suggestive of an M2-like signature. The presence of an M2-like immunoregulatory signature defined by upregulation of the IL-10 was also seen in macrophages identified post clustering of in vivo scRNA-seq data on myeloid cells. Conclusion: Using novel agonistic anti-VISTA antibodies, we reveal that VISTA triggering on myeloid cells can induce an alternative anti-inflammatory cell-state, even under conditions of strong inflammatory polarization. This introduces VISTA as an intrinsic checkpoint of macrophage tolerance. Disclosures Noelle: Immunext: Employment, Equity Ownership, Patents & Royalties, Research Funding.

scholarly journals 585 LIGHT (TNFSF14) co-stimulation enhances myeloid cell activation and anti-tumor immunity in the setting of PD-1 and TIGIT checkpoint blockade

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A615-A615
Author(s):  
George Fromm ◽  
Kyung Jin Yoo ◽  
Kellsey Johannes ◽  
Casey Shuptrine ◽  
Zach Opheim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Acquired Resistance ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Preclinical Model ◽  
And Function ◽  
Anti Tumor Activity

BackgroundCo-inhibition of TIGIT and PD-1/L1 improves response rates compared to monotherapy PD-1/L1 blockade in checkpoint naïve NSCLC with PD-L1 expression >50%. TIGIT mAbs with an effector competent Fc can induce myeloid cell activation, and some have also demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT antibody blockade translates to anti-tumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Further, DNAM-1 is downregulated on TIL in advanced and CPI resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or CPI resistant tumors, may be enhanced by immune co-stimulation that independently operates from PD-1/L1 inhibition.MethodsMouse and human TIGIT-Fc-LIGHT molecules were generated and assessed using Octet, MSD, and cell binding assays, and function was evaluated using in vitro/in vivo activation and anti-tumor efficacy experiments; including a preclinical model engineered to mimic human CPI acquired resistance.ResultsTIGIT-Fc-LIGHT was nominated using in vitro and genomic screening assays designed to identify TNF costimulatory receptors widely expressed on TIL, T stem cell memory (Tscm), and NK cells; relative to DNAM-1 expression. HVEM was prioritized, and its ligand TNFSF14 (LIGHT) also directly activates myeloid cells through binding to a second receptor, LTβR. TIGIT-Fc-LIGHT simultaneously engaged TIGIT and LIGHT receptors at low nanomolar affinities (~3.5–6.5 nM), without the requirement for an effector competent Fc. HVEM signaling overlaps with DNAM-1, and TIGIT-Fc-LIGHT activated canonical and non-canonical NFκB pathways, leading to increased tumor infiltration of antigen-specific CD8+ T and NK cells. Importantly, anti-tumor efficacy induced by monotherapy TIGIT-Fc-LIGHT was maintained in aggressive anti-PD-1 acquired resistant tumors, a model where combined PD-1 and TIGIT antibody blockade was inactive. Because HVEM lacks cytoplasmic domain homology to DNAM-1, HVEM signaling is unlikely to be regulated by PD-1. Indeed, while anti-tumor activity of TIGIT-Fc-LIGHT was enhanced by PD-1/L1 blockade, it was not dependent upon combination. TIGIT-Fc-LIGHT also directly activated myeloid cells and increased the expression of CXCL10 and CXCL11, and stimulated proinflammatory cytokines, including CCL2, CCL4, and CXCL13.ConclusionsTIGIT-Fc-LIGHT was designed to overcome the limitations of TIGIT blocking antibodies through: 1) preserved costimulation in advanced tumors, 2) direct myeloid cell activation, 3) blockade of all known TIGIT ligands, and with 4) no risk of depleting effector lymphocytes since TIGIT-Fc-LIGHT activity does not require Fc function. Pre-clinical data indicate that these goals were achieved, and further development is warranted.

scholarly journals Alzheimer’s patient brain myeloid cells exhibit enhanced aging and unique transcriptional activation

2019 ◽  
Author(s):  
Karpagam Srinivasan ◽  
Brad A. Friedman ◽  
Ainhoa Etxeberria ◽  
Melanie A. Huntley ◽  
Marcel P. van der Brug ◽  
...  
Keyword(s):  
Mouse Models ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Expression Profiles ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Differentially Expressed ◽  
Transcriptional Responses ◽  
Fresh Tissue ◽  
A Genome

AbstractGene expression changes in brain microglia from mouse models of Alzheimer’s disease (AD) are highly characterized and reflect specific myeloid cell activation states that could modulate AD risk or progression. While some groups have produced valuable expression profiles for human brain cells1–4, the cellular clarity with which we now view transcriptional responses in mouse AD models has not yet been realized for human AD tissues due to limited availability of fresh tissue samples and technological hurdles of recovering transcriptomic data with cell-type resolution from frozen samples. We developed a novel method for isolating multiple cell types from frozen post-mortem specimens of superior frontal gyrus for RNA-Seq and identified 66 genes differentially expressed between AD and control subjects in the myeloid cell compartment. Myeloid cells sorted from fusiform gyrus of the same subjects showed similar changes, and whole tissue RNA analyses further corroborated our findings. The changes we observed did not resemble the “damage-associated microglia” (DAM) profile described in mouse AD models5, or other known activation states from other disease models. Instead, roughly half of the changes were consistent with an “enhanced human aging” phenotype, whereas the other half, including the AD risk gene APOE, were altered in AD myeloid cells but not differentially expressed with age. We refer to this novel profile in human Alzheimer’s microglia/myeloid cells as the HAM signature. These results, which can be browsed at research-pub.gene.com/BrainMyeloidLandscape/reviewVersion, highlight considerable differences between myeloid activation in mouse models and human disease, and provide a genome-wide picture of brain myeloid activation in human AD.

Sign in / Sign up

Export Citation Format

Share Document