Authors: Beibei Wang, Liuluan Zhu, Bei Jia...

Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity. However, these reprogramed granulocytes exhibit "non-classic" characteristics of innate immune memory. Two mechanisms are independently involved in the innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis and chromatin remodeling leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of stressed granulocytes on anti-infection immunity might provide a strategy to fight secondary infections during sepsis.

Topics: Humans; Animals; Mice; Trained Immunity; Coinfection; Granulocytes; Sepsis; Cytokines

PubMed: 37643085
DOI: 10.1016/j.celrep.2023.113044

Authors: Christopher M Horn, Prabhakar Arumugam, Zachary Van Roy...

Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs), which are critical for orchestrating the antiinflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxia response through HIF1a were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted Hif1a conditional KO mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, single-cell RNA-Seq (scRNA-Seq) analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxia-response genes. These findings support the importance of a glycolysis/HIF1a axis in promoting G-MDSC antiinflammatory activity and biofilm persistence during PJI.

Topics: Humans; Mice; Animals; Myeloid-Derived Suppressor Cells; Staphylococcus aureus; Biofilms; Granulocytes; Hypoxia

PubMed: 38421730
DOI: 10.1172/JCI174051

Review

Authors: Luciana P Tavares, Hong Yong Peh, Wan Shun Daniel Tan...

The average respiration rate for an adult is 12-20 breaths per minute, which constantly exposes the lungs to allergens and harmful particles. As a result, respiratory diseases, which includes asthma, chronic obstructive pulmonary disease (COPD) and acute lower respiratory tract infections (LTRI), are a major cause of death worldwide. Although asthma, COPD and LTRI are distinctly different diseases with separate mechanisms of disease progression, they do share a common feature - airway inflammation with intense recruitment and activation of granulocytes and mast cells. Neutrophils, eosinophils, basophils, and mast cells are crucial players in host defense against pathogens and maintenance of lung homeostasis. Upon contact with harmful particles, part of the pulmonary defense mechanism is to recruit these cells into the airways. Despite their protective nature, overactivation or accumulation of granulocytes and mast cells in the lungs results in unwanted chronic airway inflammation and damage. As such, understanding the bright and the dark side of these leukocytes in lung physiology paves the way for the development of therapies targeting this important mechanism of disease. Here we discuss the role of granulocytes in respiratory diseases and summarize therapeutic strategies focused on granulocyte recruitment and activation in the lungs.

Topics: Animals; Chemotaxis, Leukocyte; Granulocytes; Humans; Inflammation Mediators; Molecular Targeted Therapy; Phenotype; Respiratory System; Respiratory System Agents; Respiratory Tract Diseases; Signal Transduction

PubMed: 32380052
DOI: 10.1016/j.phrs.2020.104881

Review

Authors: Gösta Berlin, Honar Cherif, Folke Knutson...

There are no randomized controlled trials proving the clinical benefit of granulocyte transfusions. However, clinical experience and a number of case studies suggest that granulocyte transfusions may be life-saving in certain situations. In our opinion granulocyte transfusions should be considered for patients with profound neutropenia and severe, life-threatening infection not responding to antibiotic or antifungal therapy. Since the clinical effect seems to be dose-dependent, the granulocyte concentrate should contain a large number of cells, which usually means that the donor should be mobilized with steroids and G-CSF. Regular blood donors as well as relatives to the patient can be used for granulocyte donations with apheresis technique after information of the process. Granulocyte transfusion should be given daily as long as the indication remains. The clinical efficacy of the transfusions should be evaluated daily.

Topics: Critical Illness; Donor Selection; Granulocytes; Humans; Infections; Leukocyte Transfusion; Neutropenia; Procedures and Techniques Utilization

PubMed: 29558012
DOI: No ID Found

Review

Authors: Sergejs Berdnikovs

It is now becoming clear that neutrophils and eosinophils are heterogeneous cells with potentially multiple subsets in health and disease. With greater marker coverage by multi-color flow cytometry and single-cell level sequencing of granulocyte populations, novel phenotypes of these cells began to emerge. Intriguingly, many newly described subsets blend distinctions between classical myeloid lineage phenotypes, which are especially true for tissue resident or recruited cells in contexts of inflammation and disease. This includes reports of neutrophils with features of eosinophils, monocytes and dendritic cells, and eosinophil subsets expressing neutrophil markers. Moreover, novel studies show the ability of immature neutrophils to transdifferentiate into mature cells belonging to other myeloid lineages (eosinophils, monocytes/macrophages). In this review, we summarize novel findings in this exciting research frontier and shed light on potential processes driving the plasticity and heterogeneity of granulocyte subsets. Specifically, we discuss the hematopoietic flexibility of granulocyte precursors in bone marrow and the adaptation of myeloid cells to local tissue microenvironments. The understanding of such intermediate and developmental phenotypes is very important, as it can teach us about origins of functionally distinct myeloid cells during inflammation, and explain reasons for successes and failures of biologics targeting terminally differentiated granulocytes.

Topics: Bone Marrow Cells; Cell Differentiation; Eosinophils; Humans; Monocytes; Myeloid Cells; Neutrophils

PubMed: 34009400
DOI: 10.1007/s00281-021-00862-z

Review

Authors: Chiara Cugno, Sara Deola, Perla Filippini...

Bacterial and fungal infections continue to pose a major clinical challenge in patients with prolonged severe neutropenia after chemotherapy or hematopoietic stem cell transplantation (HSCT). With the advent of granulocyte colony-stimulating factor (G-CSF) to mobilize neutrophils in healthy donors, granulocyte transfusions have been broadly used to prevent and/or treat life-threatening infections in patients with severe febrile neutropenia and/or neutrophil dysfunction. Although the results of randomized controlled trials are inconclusive, there are suggestions from pilot and retrospective studies that granulocyte transfusions may benefit selected categories of patients. We will critically appraise the evidence related to the use of therapeutic granulocyte transfusions in children and adults, highlighting current controversies in the field and discussing complementary approaches to modulate phagocyte function in the host.

Topics: Adult; Blood Component Transfusion; Child; Cytokines; Granulocytes; Hematologic Neoplasms; Humans; Randomized Controlled Trials as Topic

PubMed: 26572736
DOI: 10.1186/s12967-015-0724-5

Review

Authors: Caterina Giovanna Valentini, Francesca Farina, Livio Pagano...

Granulocyte transfusions (GTs) are seldom used as a life-saving therapy for neutropenic patients with severe infections. Despite compelling evidence of GT efficacy in retrospective and prospective case series, no study has been successful in demonstrating a definite advantage for recipients in controlled clinical trials. This review critically revises some aspects emerging from past experience that might have weakened the evidence of GT benefits. Some specific issues relevant to the efficacy of this therapeutic approach, such as primary infection, delivered doses and schedules, and immunologic effects of GTs, are discussed. Importantly, the awareness of biologic effects accompanying the transfusion of neutrophils might support their use at standardized doses and may definitely convey significant advantages to the recipient patients.

Topics: Cell- and Tissue-Based Therapy; Granulocytes; Humans; Infections; Neutropenia; Neutrophils; Treatment Outcome

PubMed: 28797785
DOI: 10.1016/j.bbmt.2017.07.029

Review

Authors: Leonie Fingerhut, Gaby Dolz, Nicole de Buhr...

Over the years of evolution, thousands of different animal species have evolved. All these species require an immune system to defend themselves against invading pathogens. Nevertheless, the immune systems of different species are obviously counteracting against the same pathogen with different efficiency. Therefore, the question arises if the process that was leading to the clades of vertebrates in the animal kingdom-namely mammals, birds, amphibians, reptiles, and fish-was also leading to different functions of immune cells. One cell type of the innate immune system that is transmigrating as first line of defense in infected tissue and counteracts against pathogens is the neutrophil granulocyte. During the host-pathogen interaction they can undergo phagocytosis, apoptosis, degranulation, and form neutrophil extracellular traps (NETs). In this review, we summarize a wide spectrum of information about neutrophils in humans and animals, with a focus on vertebrates. Special attention is kept on the development, morphology, composition, and functions of these cells, but also on dysfunctions and options for cell culture or storage.

Topics: Animals; Biological Evolution; Evolution, Molecular; Extracellular Traps; Granulocytes; Host-Pathogen Interactions; Humans; Immunity, Innate; Neutrophils; Phagocytosis

PubMed: 32630520
DOI: 10.3390/ijms21124523

Review

Authors: Kamille A West, Juan Gea-Banacloche, David Stroncek...

Granulocyte transfusions have a long history of being used in patients with neutropenia or neutrophil dysfunction to prevent and treat invasive fungal infections. However, there are limited and conflicting data concerning its clinical effectiveness, considerable variations in current granulocyte transfusion practices, and uncertainties about its benefit as an adjunct to modern antifungal therapy. In this review, we provide an overview on granulocyte transfusions and summarize the evidence on their role in the prevention and treatment of invasive fungal infections.

Topics: Donor Selection; Evidence-Based Medicine; Granulocytes; Humans; Invasive Fungal Infections; Leukocyte Transfusion; Neutrophils

PubMed: 28295178
DOI: 10.1111/bjh.14597

Review

Authors: Camilla Rydberg Millrud, Caroline Bergenfelz, Karin Leandersson...

Myeloid-derived suppressor cells (MDSCs) have a strong immunosuppressive character that allows them to regulate immune responses and hinder overt inflammatory responses. In cancer, this leads to tumor immune evasion and disease progression. MDSCs come in at least two forms: monocytic (Mo-MDSCs) and granulocytic (G-MDSCs). The classical definition of MDSCs as immature myeloid cells blocked from differentiating has been challenged by recent studies suggesting that Mo-MDSCs and G-MDSCs may represent monocytes and granulocytes that have acquired immunosuppressive properties. The molecular mechanism behind their generation and their true origins are now widely debated. In this review we discuss the different proposed mechanisms of the generation of both types of MDSCs, with a special focus on human MDSCs in cancer.

Topics: Animals; Cell Differentiation; Cellular Reprogramming; Colony-Stimulating Factors; Gene Expression Regulation; Granulocytes; Hematopoiesis, Extramedullary; Humans; Immunomodulation; Monocytes; Myeloid Cells; Myeloid-Derived Suppressor Cells; Myelopoiesis; Neutrophil Activation; Neutrophils; Phenotype; Signal Transduction

PubMed: 27690299
DOI: 10.18632/oncotarget.12278