• Cytokine
• Natural killer - NK

• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Animals
• Mice
• Humans
• Xenograft Model Antitumor Assays
• Cell Line, Tumor
• Culture Media, Conditioned/pharmacology
• Female

• Institute for Information and Communications Technology Promotion
• National Research Foundation of Korea

• CCR4
• CXCR4
• blood−brain barrier
• engineered living material
• glioblastoma
• natural killer cell

• Glioblastoma/therapy
• Glioblastoma/immunology
• Glioblastoma/pathology
• Killer Cells, Natural/immunology
• Humans
• Cations/chemistry
• Magnetite Nanoparticles/chemistry
• Animals
• Mice
• Cell Line, Tumor
• Brain Neoplasms/therapy
• Brain Neoplasms/immunology
• Brain Neoplasms/pathology
• Blood-Brain Barrier/metabolism
• Hyaluronic Acid/chemistry
• Polyethyleneimine/chemistry

• Adult
• Humans
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
• CD47 Antigen
• Receptors, CCR4
• Interleukin-3 Receptor alpha Subunit
• Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
• Lymphoma, B-Cell
• T-Lymphocytes/pathology
• Proto-Oncogene Proteins c-bcl-2

• atherosclerosis
• chemokine receptors
• chemokines
• regulatory T cells

• CCR5
• Chemotaxis
• Liver failure
• NK cell
• Virus infection

• Animals
• Mice
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CCL5
• Chemokines
• Chemokines, CC
• Killer Cells, Natural
• Liver Failure, Acute
• Murine hepatitis virus
• Receptors, CCR5
• Receptors, Chemokine

• 2021YFC2600200 National Key Research and Development Program of China
• 2021CFB353 Natural Science Foundation of Hubei Province
• NO. 82170596 National Natural Science Foundation of China

• CBIS
• CCR8
• flow cytometry
• immunofluorescence
• monoclonal antibody

Interactions between the nervous and immune systems control the generation and maintenance of inflammatory pain. However, the immune cells and mediators controlling this response remain poorly characterized. We identified the cytokines CCL22 and CCL17 as secreted mediators that act directly on sensory neurons to mediate postoperative pain via their shared receptor, CCR4. We also show that skin-resident dendritic cells are key contributors to the inflammatory pain response. Blocking the interaction between these dendritic cell–derived ligands and their receptor can abrogate the pain response, highlighting CCR4 antagonists as potentially effective therapies for postoperative pain. Our findings identify functions for these tissue-resident myeloid cells and uncover mechanisms underlying pain pathophysiology.

Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6C^low myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.

• cytokines
• electrophysiology
• inflammation
• myeloid cells
• pain

• CCR8
• Tregs
• cancer
• chemokine
• immunotherapy
• regulatory T cells

• MR/L018284/1 Medical Research Council

• CCL1
• CCR8
• CXCL10
• CXCL9
• cancer immunotherapy
• chemokine receptors
• chemokines
• immune checkpoint inhibitors
• regulatory T cells

• CCR8
• CD4+ T cells
• CD8+ T cells
• Foxp3
• Treg
• cancer
• immunotherapy

• PD-1 blockade
• cancer immunotherapy
• immune modulation
• immune suppression
• regulatory T (Treg) cell

• AECs, airway epithelial cells
• AP-1, Activator Protein 1
• ARDS
• ARDS, acute respiratory disease syndrome
• BALF, bronchial alveolar lavage fluid
• CAP, community acquired pneumonia
• COVID-19
• CRS, cytokine releasing syndrome
• Chemokine Receptors
• Chemokines
• DCs, dendritic cells
• ECM, extracellular matrix
• GAGs, glycosaminoglycans
• HIV, human immunodeficiency virus
• HRSV, human respiratory syncytial virus
• IFN, interferon
• IMM, inflammatory monocytes and macrophages
• IP-10, IFN-γ-inducible protein 10
• IRF, interferon regulatory factor
• Immunity
• MERS-CoV, Middle East respiratory syndrome coronavirus
• NETs, neutrophil extracellular traps
• NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells
• NK cells, natural killer cells
• PBMCs, peripheral blood mononuclear cells
• PRR, pattern recognition receptors
• RSV, rous sarcoma virus
• SARS-CoV, severe acute respiratory syndrome coronavirus
• SARS-CoV-2
• TLR, toll like receptor
• TRIF, TIR-domain-containing adapter-inducing interferon-β

• Cancer
• Immunotherapy
• Regulatory T cells
• Specificity
• Tumor microenvironment

• activation cell therapeutics
• cancer immunotherapy
• cationic nanoparticles
• natural killer (NK) cell
• tumor treatment

• Animals
• Cell Line, Tumor
• Female
• Humans
• Immunologic Factors/chemistry
• Immunologic Factors/pharmacology
• Immunotherapy/methods
• Indoles/chemistry
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/immunology
• Lymphocyte Activation/drug effects
• Mice, Nude
• Nanoparticles/chemistry
• Neoplasms/therapy
• Polyethyleneimine/chemistry
• Polyethyleneimine/pharmacology
• Polymers/chemistry
• Xenograft Model Antitumor Assays

Platelets are the primary cellular mediators of hemostasis and this function firmly acquaints them with a variety of inflammatory processes. For example, platelets can act as circulating sentinels by expressing Toll-like receptors (TLR) that bind pathogens and this allows platelets to effectively kill them or present them to cells of the immune system. Furthermore, activated platelets secrete and express many pro- and anti-inflammatory molecules that attract and capture circulating leukocytes and direct them to inflamed tissues. In addition, platelets can directly influence adaptive immune responses via secretion of, for example, CD40 and CD40L molecules. Platelets are also the source of most of the microvesicles in the circulation and these miniscule elements further enhance the platelet’s ability to communicate with the immune system. More recently, it has been demonstrated that platelets and their parent cells, the megakaryocytes (MK), can also uptake, process and present both foreign and self-antigens to CD8+ T-cells conferring on them the ability to directly alter adaptive immune responses. This review will highlight several of the non-hemostatic attributes of platelets that clearly and rightfully place them as integral players in immune reactions.

•

Platelets can act as circulating sentinels by expressing pathogen-associated molecular pattern receptors that bind pathogens and induce their killing and elimination.

• Antigen processing and presentation
• Bacteria
• CD40L
• Chemokines
• Cytokines
• Immune response
• Microvesicles
• Platelets
• TLR
• Viruses

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Surgical resection and tyrosine kinase inhibitors are defined as the main treatments but cannot cure patients with advanced GIST, which eventually develops into recurrence and acquired drug resistance. Therefore, it is necessary to identify prognostic biomarkers and new therapeutic targets for GISTs. CC chemokine receptor type 8 (CCR8) protein participates in regulation of immune responses. Recent studies on CCR8 in non-small cell lung cancer and colorectal cancer showed that it was highly expressed in tumor-infiltrating regulatory T cells and correlated with a poor prognosis.

To detect CCR8 expression in GIST tissues and analyze its relationships with clinicopathological features and prognosis in patients with GISTs.

Tissue samples were used for the tissue microarrays construction. The microarrays were then subjected to immunohistochemical analyses to detect CCR8 expression. Next, Kaplan–Meier analysis was utilized to calculate the survival rate of patients with complete follow-up data, and the potential prognostic value of CCR8 was evaluated by Cox regression analysis. Finally, a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes single-gene enrichment chart of CCR8 was constructed using the STRING database.

CCR8-positive signals were detected as brown or brown-yellow particles by immunohistochemistry located in the cytoplasm. Among 125 tissue samples, 74 had CCR8 high expression and 51 had low or negative expression. Statistical analyses suggested CCR8 was significantly correlated with tumor size, mitotic index, AFIP-Miettinen risk classification and tumor location. Kaplan–Meier and multivariate analyses showed that patients with low or negative CCR8 expression, mitotic index < 5/high-power fields (HPF) and tumor diameter < 5 cm had a better prognosis. Based on the STRING database, CCR8 was significantly enriched in biological processes such as tumor immunity, T lymphocyte chemotaxis, migration and pathways like the nuclear factor-κB and tumor necrosis factor pathways as well as intestinal immune regulation networks.

CCR8 is a prognostic biomarker for malignant potential of GISTs, with high expression correlated with malignancy and poor prognosis.

• Gastrointestinal stromal tumors
• CC chemokine receptor type 8
• Malignant phenotype
• Prognosis
• STRING database
• Immune regulation

• Biomarkers, Tumor/genetics
• Carcinoma, Non-Small-Cell Lung
• Gastrointestinal Neoplasms
• Gastrointestinal Stromal Tumors
• Humans
• Lung Neoplasms
• Neoplasm Recurrence, Local
• Prognosis
• Receptors, CCR
• Receptors, CCR8

Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD.

Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell-depleted bone marrow with or without spleen cells to generate Scl-GVHD. hMSCs were intravenously treated on days 3, 5, and 7 post-transplantation, and the control antibody or CCL1 blocking antibody was subcutaneously injected according to the same schedule as the hMSCs. Fourteen days after transplantation, the recipient mice were sacrificed, and their skin and lungs were analyzed.

After the early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs had migrated into the lungs, but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently upregulated the expression of CCL1 in the lungs, but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with the preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and upregulation of chemokines were also decreased in lung tissues, along with the recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade.

These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 upregulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.

• Allogeneic hematopoietic stem cell transplantation
• Chronic graft-versus-host disease
• Mesenchymal stem cells
• Sclerodermatous graft-versus-host disease

Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.

• evasion strategies
• human metapneumovirus
• innate and adaptive immune response

• Humans
• Immune Evasion
• Immunity, Cellular
• Immunity, Innate
• Lung/immunology
• Lung/pathology
• Lung/virology
• Metapneumovirus/immunology
• Metapneumovirus/pathogenicity
• Metapneumovirus/physiology
• Paramyxoviridae Infections/immunology
• Paramyxoviridae Infections/pathology
• Paramyxoviridae Infections/virology
• Respiratory Tract Infections/immunology
• Respiratory Tract Infections/pathology
• Respiratory Tract Infections/virology
• Virus Replication

• evasion strategies
• human metapneumovirus
• innate and adaptive immune response

Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.

• Atherosclerosis
• CCL1
• CCR8
• IL-10
• Treg

• Animals
• Apolipoproteins E/immunology
• Atherosclerosis/immunology
• Chemokine CCL1/immunology
• Cytokines/immunology
• Inflammation/immunology
• Interleukin-10/immunology
• Leukocytes/immunology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, CCR8/immunology
• T-Lymphocytes, Regulatory/immunology
• Th1 Cells/immunology
• Th2 Cells/immunology

• RG/15/11/31593 British Heart Foundation

• CCL1
• CD39
• EAE
• FOXp3
• chemokine

• Hodgkin lymphoma
• gene expression
• prognostic factors
• therapy resistance

• Adult
• Biomarkers/blood
• Chemokine CCL11/blood
• Chemokine CCL17/blood
• Chemokine CCL26
• Chemokine CCL27/blood
• Chemokines, CC/blood
• Female
• Humans
• Male
• Middle Aged
• Urticaria/immunology
• Urticaria/pathology
• Young Adult

• Dendritic cells
• Inflammation
• Neutrophils
• OX40L
• TSLP
• Viral replication
• hMPV

• Sézary syndrome
• T-helper 2-dominant microenvironment
• T-helper 22 cell
• mycosis fungoides
• tumor-associated macrophage

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/immunology
• Atherosclerosis/drug therapy
• Atherosclerosis/immunology
• Chemokines/immunology
• Humans
• Inflammation/drug therapy
• Inflammation/immunology
• Metabolic Syndrome/drug therapy
• Metabolic Syndrome/immunology
• Receptors, CCR/immunology

• PG/10/60/28496 British Heart Foundation
• RG/10/15/28578 British Heart Foundation

• Animals
• Bone Marrow Cells/immunology
• Bone Marrow Cells/metabolism
• Cell Movement/genetics
• Cell Movement/immunology
• Chemokine CCL2/metabolism
• Immunophenotyping
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Lung/cytology
• Lung/immunology
• Mice
• Mice, Knockout
• Orthomyxoviridae Infections/genetics
• Orthomyxoviridae Infections/immunology
• Orthomyxoviridae Infections/metabolism
• Receptors, CCR2/genetics
• Receptors, CCR2/metabolism
• Spleen/cytology
• Spleen/immunology

• Wellcome Trust
• WT085733MA Wellcome Trust

• Animals
• Apoptosis
• Calcium/metabolism
• Cell Line, Tumor
• Chemokine CCL1/chemistry
• Dexamethasone/pharmacology
• GPI-Linked Proteins/chemistry
• Glycosylation
• Humans
• Hydrolysis
• Inflammation
• Mass Spectrometry/methods
• Metalloendopeptidases/chemistry
• Mice
• Models, Biological
• Protein Binding
• Protein Structure, Tertiary
• Receptors, CCR8/metabolism
• Signal Transduction

• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Humans
• Interferon-gamma/metabolism
• Interleukin-1/immunology
• Interleukin-1/metabolism
• Interleukin-17/immunology
• Interleukin-17/metabolism
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Multiple Sclerosis/cerebrospinal fluid
• Multiple Sclerosis/metabolism