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CNS Neuroscience & Therapeutics Dec 2023Ischemic stroke is one of the leading causes of death worldwide and the most common cause of disability in Western countries. Multiple mechanisms contribute to the... (Review)
Review
AIMS
Ischemic stroke is one of the leading causes of death worldwide and the most common cause of disability in Western countries. Multiple mechanisms contribute to the development and progression of ischemic stroke, and inflammation is one of the most important mechanisms.
DISCUSSION
Ischemia induces the release of adenosine triphosphate/reactive oxygen species, which activates immune cells to produce many proinflammatory cytokines that activate downstream inflammatory cascades to induce fatal immune responses. Research has confirmed that peripheral blood immune cells play a vital role in the immunological cascade after ischemic stroke. The role of monocytes has received much attention among numerous peripheral blood immune cells. Monocytes induce their effects by secreting cytokines or chemokines, including CCL2/CCR2, CCR4, CCR5, CD36, CX3CL1/CX3CR1, CXCL12(SDF-1), LFA-1/ICAM-1, Ly6C, MMP-2/9, NR4A1, P2X4R, P-selectin, CD40L, TLR2/4, and VCAM-1/VLA-4. Those factors play important roles in the process of monocyte recruitment, migration, and differentiation.
CONCLUSION
This review focuses on the function and mechanism of the cytokines secreted by monocytes in the process of ischemic stroke and provides novel targets for treating cerebral ischemic stroke.
Topics: Humans; Monocytes; Cytokines; Ischemic Stroke; Stroke; Ischemia; Receptors, CCR2
PubMed: 37452512
DOI: 10.1111/cns.14368 -
Nature Feb 2024Psychosocial stress has profound effects on the body, including the immune system and the brain. Although a large number of pre-clinical and clinical studies have linked...
Psychosocial stress has profound effects on the body, including the immune system and the brain. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD), the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.
Topics: Animals; Humans; Mice; Depressive Disorder, Major; Extracellular Space; Matrix Metalloproteinase 8; Mice, Inbred C57BL; Monocytes; Nucleus Accumbens; Parenchymal Tissue; Single-Cell Gene Expression Analysis; Social Behavior; Social Isolation; Stress, Psychological
PubMed: 38326622
DOI: 10.1038/s41586-023-07015-2 -
American Journal of Physiology. Cell... Oct 2023Pulmonary fibrosis results from a plethora of abnormal pathogenetic events. In idiopathic pulmonary fibrosis (IPF), inhalational, environmental, or occupational... (Review)
Review
Pulmonary fibrosis results from a plethora of abnormal pathogenetic events. In idiopathic pulmonary fibrosis (IPF), inhalational, environmental, or occupational exposures in genetically and epigenetically predisposed individuals trigger recurrent cycles of alveolar epithelial cell injury, activation of coagulation pathways, chemoattraction, and differentiation of monocytes into monocyte-derived alveolar macrophages (Mo-AMs). When these events happen intermittently and repeatedly throughout the individual's life cycle, the wound repair process becomes aberrant leading to bronchiolization of distal air spaces, fibroblast accumulation, extracellular matrix deposition, and loss of the alveolar-capillary architecture. The role of immune dysregulation in IPF pathogenesis and progression has been underscored in the past mainly after the disappointing results of immunosuppressant use in IPF patients; however, recent reports highlighting the prognostic and mechanistic roles of monocytes and Mo-AMs revived the interest in immune dysregulation in IPF. In this review, we will discuss the role of these cells in the onset and progression of IPF, as well as potential targeted therapies.
Topics: Humans; Monocytes; Idiopathic Pulmonary Fibrosis; Macrophages; Extracellular Matrix; Cell Differentiation; Lung
PubMed: 37694283
DOI: 10.1152/ajpcell.00302.2023 -
The Journal of Experimental Medicine Aug 2023Obesity is characterized by chronic systemic inflammation and enhances cancer metastasis and mortality. Obesity promotes breast cancer metastasis to lung in a...
Obesity is characterized by chronic systemic inflammation and enhances cancer metastasis and mortality. Obesity promotes breast cancer metastasis to lung in a neutrophil-dependent manner; however, the upstream regulatory mechanisms of this process remain unknown. Here, we show that obesity-induced monocytes underlie neutrophil activation and breast cancer lung metastasis. Using mass cytometry, obesity favors the expansion of myeloid lineages while restricting lymphoid cells within the peripheral blood. RNA sequencing and flow cytometry revealed that obesity-associated monocytes resemble professional antigen-presenting cells due to a shift in their development and exhibit enhanced MHCII expression and CXCL2 production. Monocyte induction of the CXCL2-CXCR2 axis underlies neutrophil activation and release of neutrophil extracellular traps to promote metastasis, and enhancement of this signaling axis is observed in lung metastases from obese cancer patients. Our findings provide mechanistic insight into the relationship between obesity and cancer by broadening our understanding of the interactive role that myeloid cells play in this process.
Topics: Humans; Female; Monocytes; Lung Neoplasms; Obesity; Myeloid Cells; Breast Neoplasms; Inflammation
PubMed: 37166450
DOI: 10.1084/jem.20220509 -
Nature Communications Sep 2023Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving...
Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.
Topics: Humans; Male; Animals; Mice; Monocytes; Immunosuppression Therapy; Aggression; Immune Checkpoint Inhibitors; Colorectal Neoplasms; Tumor Microenvironment
PubMed: 37749092
DOI: 10.1038/s41467-023-41095-y -
Redox Biology Aug 2023Endothelial dysfunction results in chronic vascular inflammation, which is critical for the development of atherosclerotic diseases. Transcription factor Gata6 has been...
Endothelial dysfunction results in chronic vascular inflammation, which is critical for the development of atherosclerotic diseases. Transcription factor Gata6 has been reported to regulate vascular endothelial cell activation and inflammation in vitro. Here, we aimed to explore the roles and mechanisms of endothelial Gata6 in atherogenesis. Endothelial cell (EC) specific Gata6 deletion was generated in the Apoe hyperlipidemic atherosclerosis mouse model. Atherosclerotic lesion formation, endothelial inflammatory signaling, and endothelial-macrophage interaction were examined in vivo and in vitro by using cellular and molecular biological approaches. EC-GATA6 deletion mice exhibited a significant decrease in monocyte infiltration and atherosclerotic lesion compared to littermate control mice. Cytosine monophosphate kinase 2 (Cmpk2) was identified as a direct target gene of GATA6 and EC-GATA6 deletion decreased monocyte adherence, migration and pro-inflammatory macrophage foam cell formation through regulation of the CMPK2-Nlrp3 pathway. Endothelial target delivery of Cmpk2-shRNA by intercellular adhesion molecule 2 (Icam-2) promoter-driven AAV9 carrying the shRNA reversed the Gata6 upregulation mediated elevated Cmpk2 expression and further Nlrp3 activation and thus attenuated atherosclerosis. In addition, C-C motif chemokine ligand 5 (Ccl5) was also identified as a direct target gene of Gata6 to regulate monocyte adherence and migration influencing atherogenesis. This study provides direct in vivo evidence of EC-GATA6 involvement in the regulation of Cmpk2-Nlrp3, as well as Ccl5, on monocyte adherence and migration in atherosclerosis development and advances our understanding of the in vivo mechanisms of atherosclerotic lesion development, and meanwhile provides opportunities for future therapeutic interventions.
Topics: Animals; Mice; Atherosclerosis; Cell Adhesion; Inflammation; Macrophages; Mice, Inbred C57BL; Monocytes; NLR Family, Pyrin Domain-Containing 3 Protein; RNA, Small Interfering; Vascular Cell Adhesion Molecule-1
PubMed: 37339559
DOI: 10.1016/j.redox.2023.102775 -
Cardiovascular Research Jul 2023Accumulation of mononuclear phagocytes [monocytes, macrophages, and dendritic cells (DCs)] in the vessel wall is a hallmark of atherosclerosis. Using integrated...
AIMS
Accumulation of mononuclear phagocytes [monocytes, macrophages, and dendritic cells (DCs)] in the vessel wall is a hallmark of atherosclerosis. Using integrated single-cell analysis of mouse and human atherosclerosis, we here aimed to refine the nomenclature of mononuclear phagocytes in atherosclerotic vessels and to compare their transcriptomic profiles in mouse and human disease.
METHODS AND RESULTS
We integrated 12 single-cell RNA-sequencing (scRNA-seq) datasets of immune cells isolated from healthy or atherosclerotic mouse aortas, and data from 11 patients (n = 4 coronary vessels, n = 7 carotid endarterectomy specimens) from two studies. Integration of mouse data identified subpopulations with discrete transcriptomic signatures within previously described populations of aortic resident (Lyve1), inflammatory (Il1b), as well as foamy (Trem2hi) macrophages. We identified unique transcriptomic features distinguishing aortic intimal resident macrophages from atherosclerosis-associated Trem2hi macrophages. Also, populations of Xcr1+ Type 1 classical DCs (cDC1), Cd209a+ cDC2, and mature DCs (Ccr7, Fscn1) with a 'mreg-DC' signature were detected. In humans, we uncovered macrophage and DC populations with gene expression patterns similar to those observed in mice. In particular, core transcripts of the foamy/Trem2hi signature (TREM2, SPP1, GPNMB, CD9) mapped to a specific population of macrophages in human lesions. Comparison of mouse and human data and direct cross-species data integration suggested transcriptionally similar macrophage and DC populations in mice and humans.
CONCLUSIONS
We refined the nomenclature of mononuclear phagocytes in mouse atherosclerotic vessels, and show conserved transcriptomic features of macrophages and DCs in atherosclerosis in mice and humans, emphasizing the relevance of mouse models to study mononuclear phagocytes in atherosclerosis.
Topics: Humans; Macrophages; Monocytes; Atherosclerosis; Dendritic Cells; Single-Cell Analysis; Membrane Glycoproteins
PubMed: 36190844
DOI: 10.1093/cvr/cvac161 -
International Journal of Molecular... Sep 2023Cardiovascular disease, particularly coronary artery disease (CAD), remains a predominant cause of mortality globally. Factors such as atherosclerosis and inflammation... (Review)
Review
Assessment of Inflammatory Hematological Ratios (NLR, PLR, MLR, LMR and Monocyte/HDL-Cholesterol Ratio) in Acute Myocardial Infarction and Particularities in Young Patients.
Cardiovascular disease, particularly coronary artery disease (CAD), remains a predominant cause of mortality globally. Factors such as atherosclerosis and inflammation play significant roles in the pathogenesis of CAD. The nexus between inflammation and CAD is underscored by the role of immune cells, such as neutrophils, lymphocytes, monocytes, and macrophages. These cells orchestrate the inflammatory process, a core component in the initiation and progression of atherosclerosis. The activation of these pathways and the subsequent lipid, fibrous element, and calcification accumulation can result in vessel narrowing. Hematological parameters derived from routine blood tests offer insights into the underlying inflammatory state. Recent studies have highlighted the potential of inflammatory hematological ratios, such as the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio and lymphocyte/monocyte ratio. These parameters are not only accessible and cost-effective but also mirror the degree of systemic inflammation. Several studies have indicated a correlation between these markers and the severity, prognosis, and presence of CAD. Despite the burgeoning interest in the relationship between inflammatory markers and CAD, there remains a paucity of data exploring these parameters in young patients with acute myocardial infarction. Such data could offer valuable insights into the unique pathophysiology of early-onset CAD and improve risk assessment and predictive strategies.
Topics: Humans; Monocytes; Myocardial Infarction; Coronary Artery Disease; Atherosclerosis; Cholesterol
PubMed: 37762680
DOI: 10.3390/ijms241814378 -
Cell Reports Oct 2023The immune system plays a critical role during myocardial injury, contributing to repair and remodeling post myocardial infarction (MI). The myocardial infarct and...
The immune system plays a critical role during myocardial injury, contributing to repair and remodeling post myocardial infarction (MI). The myocardial infarct and border zone exhibit high heterogeneity, in turn leading to reconstructing macrophage subsets and specific functions. Here we use a combination of single-cell RNA sequencing, spatial transcriptomes, and reporter mice to characterize temporal-spatial dynamics of cardiac macrophage subtype in response to MI. We identify that transient appearance of monocyte-derived Bhlhe41 Mφs in the "developing" infarct zone peaked at day 7, while other monocyte-derived macrophages are identified in "old" infarct zone. Functional characterization by co-culture of Bhlhe41 Mφs with cardiomyocytes and fibroblasts or depletion of Bhlhe41 Mφs unveils a crucial contribution of Bhlhe41 Mφs in suppression of myofibroblast activation. This work highlights the importance of Bhlhe41 Mφ phenotype and plasticity in preventing excessive fibrosis and limiting the expansion of developing infarct area.
Topics: Mice; Animals; Myocardium; Macrophages; Myocardial Infarction; Heart; Monocytes; Mice, Inbred C57BL
PubMed: 37751357
DOI: 10.1016/j.celrep.2023.113174 -
Cell Reports Oct 2023Healthy Kupffer cell (KC) pool is dominated by embryonic KCs (EmKCs), preserving liver homeostasis. How the KC pool varies upon injury remains unclear. Using chimeric...
Healthy Kupffer cell (KC) pool is dominated by embryonic KCs (EmKCs), preserving liver homeostasis. How the KC pool varies upon injury remains unclear. Using chimeric mice with bone marrow (BM) cells labeled with enhanced green fluorescent protein, we identify that BM monocyte-derived KCs (MoKCs) become dominant in cholestatic- or toxic-injured livers via immunofluorescence and mass cytometry. Single-cell RNA sequencing (scRNA-seq) unveils the enhanced proliferative, anti-apoptotic properties and repair potential of MoKCs compared with EmKCs, which are confirmed in vivo and ex vivo through flow cytometry, qPCR, Cell Counting Kit-8, and immunofluorescence. Furthermore, compared with EmKC-dominated livers, MoKC-dominated livers exhibit less functional damage, necrosis, and fibrosis under damage, as tested by serum alanine aminotransferase activity detection, H&E and Sirius red staining, qPCR, and western blot. Collectively, we highlight that MoKCs dominate the KC pool in injured livers and show enhanced proliferative and anti-apoptotic properties while also promoting repair and attenuating fibrosis.
Topics: Mice; Animals; Kupffer Cells; Monocytes; Liver; Necrosis; Fibrosis
PubMed: 37740916
DOI: 10.1016/j.celrep.2023.113164