ABSTRACT
CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.
ABSTRACT
Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.
Subject(s)
Disease Resistance , Neoplasms/pathology , Neutrophils/immunology , Sarcoma/pathology , T-Lymphocytes/metabolism , Animals , Chromones/toxicity , Disease Resistance/immunology , Humans , Immunity, Innate , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-12/genetics , Interleukin-12/metabolism , Kaplan-Meier Estimate , Macrophages/immunology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/immunology , Neoplasms/mortality , Neutrophil Infiltration , Neutrophils/cytology , Neutrophils/metabolism , Receptors, Colony-Stimulating Factor/metabolism , Sarcoma/chemically induced , Sarcoma/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor MicroenvironmentABSTRACT
PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation.
Subject(s)
C-Reactive Protein/genetics , C-Reactive Protein/metabolism , Inflammation/metabolism , Neoplasms/immunology , Serum Amyloid P-Component/genetics , Serum Amyloid P-Component/metabolism , Animals , Complement System Proteins/metabolism , DNA Methylation , Genes, p53 , Humans , Mice , MutationABSTRACT
Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , Inflammation/immunology , Neoplasms/immunology , Tumor Escape/immunology , Animals , Dinoprostone/metabolism , Humans , Immunotherapy , Inflammation/genetics , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Mice , Neoplasms/therapy , Phenotype , Prognosis , Prostaglandin-Endoperoxide Synthases/genetics , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Receptors, Prostaglandin E, EP4 Subtype/metabolism , T-Lymphocytes, Cytotoxic/immunology , Tumor Microenvironment/immunologyABSTRACT
Neutrophils are essential soldiers of the immune response and their role have long been restricted to their activities in defence against microbial infections and during the acute phase of the inflammatory response. However, increasing number of investigations showed that neutrophils are endowed with plasticity and can participate in the orchestration of both innate and adaptive immune responses. Neutrophils have an impact on a broad range of disorders, including infections, chronic inflammations, and cancer. Neutrophils are present in the tumour microenvironment and have been reported to mediate both pro-tumour and anti-tumour responses. Neutrophils can contribute to genetic instability, tumour cell proliferation, angiogenesis and suppression of the anti-tumour immune response. In contrast, neutrophils are reported to mediate anti-tumour resistance by direct killing of tumour cells or by engaging cooperative interactions with other immune cells. Here we discuss the current understandings of neutrophils biology and functions in health and diseases, with a specific focus on their role in cancer biology and their prognostic significance in human cancer.
Subject(s)
Inflammation/immunology , Neoplasms/immunology , Neutrophils/immunology , Adaptive Immunity , Animals , Biodiversity , Humans , Immunity, Innate , Phenotype , Tumor MicroenvironmentABSTRACT
Immunity in the urinary tract has distinct and poorly understood pathophysiological characteristics and urinary tract infections (UTIs) are important causes of morbidity and mortality. We investigated the role of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, in UTIs. PTX3-deficient mice showed defective control of UTIs and exacerbated inflammation. Expression of PTX3 was induced in uroepithelial cells by uropathogenic Escherichia coli (UPEC) in a Toll-like receptor 4 (TLR4)- and MyD88-dependent manner. PTX3 enhanced UPEC phagocytosis and phagosome maturation by neutrophils. PTX3 was detected in urine of UTI patients and amounts correlated with disease severity. In cohorts of UTI-prone patients, PTX3 gene polymorphisms correlated with susceptibility to acute pyelonephritis and cystitis. These results suggest that PTX3 is an essential component of innate resistance against UTIs. Thus, the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against UTIs.
Subject(s)
C-Reactive Protein/metabolism , Escherichia coli Infections/immunology , Escherichia coli/immunology , Neutrophils/immunology , Pyelonephritis/immunology , Receptors, Pattern Recognition/metabolism , Serum Amyloid P-Component/metabolism , Urinary Tract Infections/immunology , Animals , C-Reactive Protein/genetics , Cell Line , Child , DNA Mutational Analysis , Disease Models, Animal , Escherichia coli Infections/complications , Female , Genetic Predisposition to Disease , Genotype , Humans , Immunity, Innate , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Neutrophils/microbiology , Phagocytosis , Polymorphism, Genetic , Pyelonephritis/etiology , Receptors, Pattern Recognition/genetics , Serum Amyloid P-Component/genetics , Sweden , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Urinary Tract Infections/complicationsABSTRACT
Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection.
Subject(s)
Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Liver Neoplasms/immunology , Muromegalovirus/immunology , Receptors, Interleukin-1/immunology , Animals , Cell Differentiation/genetics , Female , Herpesviridae Infections/genetics , Herpesviridae Infections/immunology , Humans , Killer Cells, Natural/metabolism , Liver Neoplasms/genetics , Lymphocyte Activation/genetics , Male , Mice , Mice, Inbred C57BL , Neoplasm Metastasis/genetics , Neoplasm Metastasis/immunology , Receptors, Interleukin-1/geneticsABSTRACT
Shigella spp. are pathogenic bacteria that cause bacillary dysentery in humans by invading the colonic and rectal mucosa where they induce dramatic inflammation. Here, we have analyzed the role of the soluble PRR Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity. Mice that had been intranasally infected with S. flexneri were rescued from death by treatment with recombinant PTX3. In vitro PTX3 exerts the antibacterial activity against Shigella, impairing epithelial cell invasion and contributing to the bactericidal activity of serum. PTX3 is produced upon LPS-TLR4 stimulation in accordance with the lipid A structure of Shigella. In the plasma of infected patients, the level of PTX3 amount only correlates strongly with symptom severity. These results signal PTX3 as a novel player in Shigella pathogenesis and its potential role in fighting shigellosis. Finally, we suggest that the plasma level of PTX3 in shigellosis patients could act as a biomarker for infection severity.
Subject(s)
C-Reactive Protein/immunology , Dysentery, Bacillary/immunology , Immunity, Innate/immunology , Serum Amyloid P-Component/immunology , Shigella flexneri/immunology , Animals , Humans , Mice , Mice, Inbred C57BLABSTRACT
The innate immune system comprises both a cellular and a humoral arm. Neutrophils are key effector cells of the immune and inflammatory responses and have emerged as a major source of humoral pattern recognition molecules (PRMs). These molecules, which include collectins, ficolins, and pentraxins, are specialised in the discrimination of self versus non-self and modified-self and share basic multifunctional properties including recognition and opsonisation of pathogens and apoptotic cells, activation and regulation of the complement cascade and tuning of inflammation. Neutrophils act as a reservoir of ready-made soluble PRMs, such as the long pentraxin PTX3, the peptidoglycan recognition protein PGRP-S, properdin and M-ficolin, which are stored in neutrophil granules and are involved in neutrophil effector functions. In addition, other soluble PRMs, such as members of the collectin family, are not expressed in neutrophils but can modulate neutrophil-dependent immune responses. Therefore, soluble PRMs are an essential part of the innate immune response and retain antibody-like effector functions. Here, we will review the expression and general function of soluble PRMs, focusing our attention on molecules involved in neutrophil effector functions.
Subject(s)
Immunity, Innate , Neutrophil Activation/immunology , Neutrophils/immunology , Neutrophils/metabolism , Animals , Biomarkers , Gene Expression Regulation , Humans , Immunity, Humoral , Ligands , Neutrophil Activation/genetics , Protein Binding , Receptors, Pattern Recognition/genetics , Receptors, Pattern Recognition/metabolism , Signal TransductionABSTRACT
Inflammatory cells are an essential component of the tumor microenvironment. Neutrophils have emerged as important players in the orchestration and effector phase of innate and adaptive immunity. The significance of tumor-associated neutrophils (TAN) in colorectal cancer (CRC) has been the subject of conflicting reports and the present study was designed to set up a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. CD66b and myeloperoxidase (MPO) were assessed as candidate neutrophil markers in CRC using immunohistochemistry. CD66b was found to be a reliable marker to identify TAN in CRC tissues, whereas MPO also identified a subset of CD68(+) macrophages. CRC patients (n = 271) (Stages I-IV) were investigated retrospectively by computer-assisted imaging on whole tumor sections. TAN density dramatically decreases in Stage IV patients as compared to Stage I-III. At Cox analysis, higher TAN density was associated with better prognosis. Importantly, multivariate analysis showed that prognostic significance of TAN can be influenced by clinical stage and 5-fluorouracil(5-FU)-based chemotherapy. On separate analysis of Stage III patients (n = 178), TAN density had a dual clinical significance depending on the use of 5-FU-based chemotherapy. Unexpectedly, higher TAN density was associated with better response to 5-FU-based chemotherapy. Thus, TAN are an important component of the immune cell infiltrate in CRC and assessment of TAN infiltration may help identify patients likely to benefit from 5-FU-based chemotherapy. These results call for a reassessment of the role of neutrophils in cancer using rigorous quantitative methodology.
Subject(s)
Colorectal Neoplasms/pathology , Neutrophil Infiltration , Neutrophils/pathology , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/mortality , Disease Progression , Female , Humans , Male , Microsatellite Repeats , Middle Aged , Neoplasm Staging , Neutrophils/metabolism , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Survival AnalysisABSTRACT
Newborns and infants present a higher susceptibility to infection than adults, a vulnerability associated with deficiencies in both the innate and adaptive immune systems. Innate immune receptors are sensors involved in the recognition and elimination of microbes that play a pivotal role at the interface between innate and adaptive immunity. Pentraxin 3 (PTX3), the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against selected pathogens. Because neonates are generally resistant to these pathogens, we suspected that PTX3 may be provided by a maternal source during the early life times. We observed that human colostrum contains high levels of PTX3, and that mammary epithelial cell and CD11b(+) milk cells constitutively produce PTX3. Interestingly, PTX3 given orally to neonate mice was rapidly distributed in different organs, and PTX3 ingested during lactation was detected in neonates. Finally, we observed that orally administered PTX3 provided protection against Pseudomonas aeruginosa lung infection in neonate mice. Therefore, breastfeeding constitutes, during the early life times, an important source of PTX3, which actively participates in the protection of neonates against infections. In addition, these results suggest that PTX3 might represent a therapeutic tool for treating neonatal infections and support the view that breastfeeding has beneficial effects on the neonates' health.
Subject(s)
Breast Feeding , C-Reactive Protein/physiology , Colostrum/chemistry , Infant, Newborn/immunology , Milk, Human/chemistry , Pneumonia, Bacterial/prevention & control , Pseudomonas Infections/prevention & control , Serum Amyloid P-Component/physiology , Administration, Oral , Adult , Animals , Animals, Newborn , Breast/cytology , C-Reactive Protein/administration & dosage , C-Reactive Protein/analysis , C-Reactive Protein/biosynthesis , C-Reactive Protein/pharmacokinetics , CD11b Antigen/analysis , Cell Line , Dendritic Cells/drug effects , Dendritic Cells/immunology , Endotoxins/pharmacology , Endotoxins/toxicity , Epithelial Cells/metabolism , Female , Humans , Lactation , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Milk, Human/cytology , Monocytes/drug effects , Monocytes/immunology , Nerve Tissue Proteins/biosynthesis , Serum Amyloid P-Component/administration & dosage , Serum Amyloid P-Component/analysis , Serum Amyloid P-Component/pharmacokinetics , Specific Pathogen-Free Organisms , Tissue DistributionABSTRACT
The innate immune system is composed of a cellular arm and a humoral arm. Components of the humoral arm include members of the complement cascade and soluble pattern recognition molecules (PRMs). These PRMs recognize pathogen-associated molecular patterns and are functional ancestors of antibodies, playing a role in complement activation, opsonization and agglutination. Pentraxins consist of a set of multimeric soluble proteins and represent the prototypic components of humoral innate immunity. The prototypic long pentraxin PTX3 is highly conserved in evolution and produced by somatic and innate immune cells after proinflammatory stimuli. PTX3 interacts with a set of self, nonself and modified self ligands and exerts essential roles in innate immunity, inflammation control and matrix deposition. In addition, translational studies suggest that PTX3 may be a useful biomarker of human pathologies complementary to C-reactive protein. In this study, we will review the general functions of pentraxins in innate immunity and inflammation, focusing our attention on the prototypic long pentraxin PTX3.
Subject(s)
Biomarkers/metabolism , C-Reactive Protein/metabolism , Infections/diagnosis , Inflammation/immunology , Neoplasms/diagnosis , Serum Amyloid P-Component/metabolism , Animals , Biological Evolution , C-Reactive Protein/genetics , Complement Activation , Conserved Sequence/genetics , Humans , Immunity, Innate , Receptors, Pattern Recognition/immunology , Serum Amyloid P-Component/geneticsABSTRACT
The tumor microenvironment is composed of tumor cells, stromal cells and leukocytes, including innate and adaptive immune cells, and represents an ecological niche that regulates tumor development and progression. In general, inflammatory cells are considered to contribute to tumor progression through various mechanisms, including the formation of an immunosuppressive microenvironment. Macrophages and neutrophils are important components of the tumor microenvironment and can act as a double-edged sword, promoting or inhibiting the development of the tumor. Targeting of the immune system is emerging as an important therapeutic strategy for cancer patients. However, the efficacy of the various immunotherapies available is still limited. Given the crucial importance of the crosstalk between macrophages and neutrophils and other immune cells in the formation of the anti-tumor immune response, targeting these interactions may represent a promising therapeutic approach against cancer. Here we will review the current knowledge of the role played by macrophages and neutrophils in cancer, focusing on their interaction with other immune cells.
Subject(s)
Neoplasms , Neutrophils , Humans , Macrophages , Immunity , Immunotherapy , Tumor MicroenvironmentABSTRACT
Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway.
Subject(s)
Colitis, Ulcerative , Colitis-Associated Neoplasms , Neutrophils , Animals , Humans , Mice , Carcinogenesis , Colitis/pathology , Colitis, Ulcerative/metabolism , Colitis-Associated Neoplasms/pathology , Disease Models, Animal , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/immunology , Neutrophils/metabolismABSTRACT
Tumor-associated macrophages (TAMs) are a key component of the tumor microenvironment and orchestrate various aspects of cancer. Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to distinct signals macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a spectrum of activation states. Metabolic adaptation is a key component of macrophage plasticity and polarization, instrumental to their function in homeostasis, immunity and inflammation. Generally, TAMs acquire an M2-like phenotype that plays important roles in many aspects of tumor growth and progression. There is now evidence that also neutrophils can be driven towards distinct phenotypes in response to microenvironmental signals. The identification of mechanisms and molecules associated with macrophage and neutrophil plasticity and polarized activation provides a basis for new diagnostic and therapeutic strategies.
Subject(s)
Macrophages/immunology , Neoplasms/immunology , Neutrophils/immunology , Animals , Disease Progression , Humans , Macrophages/classification , Macrophages/pathology , Mice , Neoplasms/blood supply , Neoplasms/pathology , Neovascularization, Pathologic , Neutrophils/pathology , Tumor Microenvironment/immunologyABSTRACT
The long pentraxin (PTX) 3 is produced by macrophages and myeloid dendritic cells in response to Toll-like receptor agonists and represents a nonredundant component of humoral innate immunity against selected pathogens. We report that, unexpectedly, PTX3 is stored in specific granules and undergoes release in response to microbial recognition and inflammatory signals. Released PTX3 can partially localize in neutrophil extracellular traps formed by extruded DNA. Eosinophils and basophils do not contain preformed PTX3. PTX3-deficient neutrophils have defective microbial recognition and phagocytosis, and PTX3 is nonredundant for neutrophil-mediated resistance against Aspergillus fumigatus. Thus, neutrophils serve as a reservoir, ready for rapid release, of the long PTX3, a key component of humoral innate immunity with opsonic activity.
Subject(s)
C-Reactive Protein/metabolism , Cytoplasmic Granules/metabolism , Extracellular Space/metabolism , Neutrophils/cytology , Serum Amyloid P-Component/metabolism , Animals , C-Reactive Protein/deficiency , C-Reactive Protein/genetics , Cells, Cultured , Gene Expression Regulation , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/metabolism , Protein Binding , Serum Amyloid P-Component/deficiency , Serum Amyloid P-Component/geneticsABSTRACT
Increasing evidence suggests that neutrophils may participate in the regulation of adaptive immune responses, and can reach draining lymph nodes and cross-prime naive T cells. The aim of this study was to identify the mechanism(s) involved in the migration of neutrophils to the draining lymph nodes. We demonstrate that a subpopulation of human and mouse neutrophils express CCR7. CCR7 is rapidly expressed at the membrane upon stimulation. In vitro, stimulated human neutrophils migrate in response to the CCR7 ligands CCL19 and CCL21. In vivo, injection of complete Freund adjuvant induces a rapid recruitment of neutrophils to the lymph nodes in wild-type mice but not in Ccr7(-/-) mice. Moreover, intradermally injected interleukin-17-and granulocyte-macrophage colony-stimulating factor-stimulated neutrophils from wild-type mice, but not from Ccr7(-/-) mice, migrate to the draining lymph nodes. These results identify CCR7 as a chemokine receptor involved in the migration of neutrophils to the lymph nodes.
Subject(s)
Cell Movement/genetics , Chemotaxis, Leukocyte/genetics , Lymph Nodes/cytology , Neutrophils/physiology , Receptors, CCR7/physiology , Animals , Cell Movement/immunology , Cells, Cultured , Humans , Lymph Nodes/immunology , Lymph Nodes/metabolism , Lymph Nodes/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration/genetics , Neutrophils/immunology , Neutrophils/metabolism , Receptors, CCR7/genetics , Receptors, CCR7/metabolismABSTRACT
The innate immune system consists of a cellular arm and a humoral arm. Components of humoral immunity include diverse molecular families, which represent functional ancestors of antibodies. They play a key role as effectors and modulators of innate resistance in animals and humans, interacting with cellular innate immunity. The prototypic long pentraxin, pentraxin 3 (PTX3), represents a case in point of this interplay. Gene targeting of this evolutionarily conserved long pentraxin has unequivocally defined its role at the crossroads of innate immunity, inflammation, matrix deposition, and female fertility. Phagocytes represent a key source of this fluid-phase pattern recognition receptor, which, in turn, facilitates microbial recognition by phagocytes acting as an opsonin. Moreover, PTX3 has modulatory functions on innate immunity and inflammation. Here, we review the studies on PTX3 which emphasize the complexity and complementarity of the crosstalk between the cellular and humoral arms of innate immunity.
Subject(s)
Acute-Phase Proteins/immunology , Acute-Phase Proteins/metabolism , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , Immunity, Cellular , Immunity, Innate , Serum Amyloid P-Component/immunology , Serum Amyloid P-Component/metabolism , Acute-Phase Proteins/chemistry , Acute-Phase Proteins/genetics , Animals , Bacterial Infections/blood , Bacterial Infections/immunology , Bacterial Infections/prevention & control , C-Reactive Protein/chemistry , C-Reactive Protein/genetics , Female , Humans , Mice , Neutrophils/immunology , Neutrophils/metabolism , Phagocytosis/immunology , Receptors, Pattern Recognition/chemistry , Receptors, Pattern Recognition/genetics , Receptors, Pattern Recognition/immunology , Receptors, Pattern Recognition/metabolism , Serum Amyloid P-Component/chemistry , Serum Amyloid P-Component/geneticsABSTRACT
Neutrophils are the most abundant circulating leukocytes in humans and the first immune cells recruited at the site of inflammation. Classically perceived as short-lived effector cells with limited plasticity and diversity, neutrophils are now recognized as highly heterogenous immune cells, which can adapt to various environmental cues. In addition to playing a central role in the host defence, neutrophils are involved in pathological contexts such as inflammatory diseases and cancer. The prevalence of neutrophils in these conditions is usually associated with detrimental inflammatory responses and poor clinical outcomes. However, a beneficial role for neutrophils is emerging in several pathological contexts, including in cancer. Here we will review the current knowledge of neutrophil biology and heterogeneity in steady state and during inflammation, with a focus on the opposing roles of neutrophils in different pathological contexts.
Subject(s)
Neoplasms , Neutrophils , Humans , Inflammation , Leukocytes/pathologyABSTRACT
Toll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulator in vivo under different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused by Pseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acute P. aeruginosa infection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], IL-1ß, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense against P. aeruginosa acute lung infection can be improved by blocking IL-1 since exaggerated IL-1ß production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8-/- IL-1RI-/- double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused by P. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.