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1.
Immunity ; 52(2): 342-356.e6, 2020 02 18.
Article in English | MEDLINE | ID: mdl-32023490

ABSTRACT

Interleukin-17A (IL-17A) is a major mediator of tissue inflammation in many autoimmune diseases. Anti-IL-17A is an effective treatment for psoriasis and is showing promise in clinical trials in multiple sclerosis. In this study, we find that IL-17A-defective mice or mice treated with anti-IL-17A at induction of experimental autoimmune encephalomyelitis (EAE) are resistant to disease and have defective priming of IL-17-secreting γδ T (γδT17) cells and Th17 cells. However, T cells from Il17a-/- mice induce EAE in wild-type mice following in vitro culture with autoantigen, IL-1ß, and IL-23. Furthermore, treatment with IL-1ß or IL-17A at induction of EAE restores disease in Il17a-/- mice. Importantly, mobilization of IL-1ß-producing neutrophils and inflammatory monocytes and activation of γδT17 cells is reduced in Il17a-/- mice. Our findings demonstrate that a key function of IL-17A in central nervous system (CNS) autoimmunity is to recruit IL-1ß-secreting myeloid cells that prime pathogenic γδT17 and Th17 cells.


Subject(s)
Autoimmunity/immunology , Interleukin-17/immunology , Interleukin-1beta/metabolism , Intraepithelial Lymphocytes/immunology , Myeloid Cells/immunology , Th17 Cells/immunology , Animals , Autoantigens/immunology , Autoimmunity/genetics , Central Nervous System/immunology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Interleukin-17/antagonists & inhibitors , Interleukin-17/deficiency , Interleukin-17/metabolism , Interleukin-1beta/immunology , Interleukin-23/immunology , Interleukin-23/metabolism , Intraepithelial Lymphocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Monocytes/metabolism , Myeloid Cells/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Th17 Cells/metabolism
2.
Semin Immunol ; 54: 101523, 2021 04.
Article in English | MEDLINE | ID: mdl-34776300

ABSTRACT

Granulocyte macrophage-colony stimulating factor (GM-CSF) was originally identified as a growth factor for its ability to promote the proliferation and differentiation in vitro of bone marrow progenitor cells into granulocytes and macrophages. Many preclinical studies, using GM-CSF deletion or depletion approaches, have demonstrated that GM-CSF has a wide range of biological functions, including the mediation of inflammation and pain, indicating that it can be a potential target in many inflammatory and autoimmune conditions. This review provides a brief overview of GM-CSF biology and signaling, and summarizes the findings from preclinical models of a range of inflammatory and autoimmune disorders and the latest clinical trials targeting GM-CSF or its receptor in these disorders.


Subject(s)
Autoimmune Diseases , Granulocyte-Macrophage Colony-Stimulating Factor , Autoimmune Diseases/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Granulocytes/metabolism , Humans , Inflammation , Macrophages
3.
Osteoarthritis Cartilage ; 32(11): 1413-1418, 2024 Nov.
Article in English | MEDLINE | ID: mdl-38844159

ABSTRACT

OBJECTIVE: We have previously reported that the interleukin-23 p19 subunit (IL-23p19) is required for experimental inflammatory arthritic pain-like behavior and disease. Even though inflammation is often a characteristic feature of osteoarthritis (OA), IL-23 is not usually considered as a therapeutic target in OA. We began to explore the role of IL-23p19 in OA pain and disease utilizing mouse models of OA and patient samples. DESIGN: The role of IL-23p19 in two mouse models of OA, namely collagenase-induced OA and monosodium iodoacetate-induced OA, was investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. In knee synovial tissues from a small cohort of human OA patients, a correlation analysis was performed between IL-23A gene expression and Oxford knee score (OKS), a validated Patient Reported Outcome Measure. RESULTS: We present evidence that i) IL-23p19 is required for the development of pain-like behavior and optimal disease, including cartilage damage and osteophyte formation, in two experimental OA models and ii) IL-23A gene expression in OA knee synovial tissues correlates with a lower OKS (r = -0.742, p = 0.0057). CONCLUSIONS: The findings support the possible targeting of IL-23 as a treatment for OA pain and disease progression.


Subject(s)
Interleukin-23 Subunit p19 , Osteoarthritis, Knee , Animals , Male , Osteoarthritis, Knee/metabolism , Osteoarthritis, Knee/genetics , Humans , Mice , Interleukin-23 Subunit p19/genetics , Interleukin-23 Subunit p19/metabolism , Synovial Membrane/metabolism , Synovial Membrane/pathology , Arthritis, Experimental/metabolism , Disease Models, Animal , Arthralgia/genetics , Arthralgia/metabolism , Pain/etiology , Pain/metabolism , Mice, Knockout , Middle Aged , Aged , Female , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Iodoacetic Acid
4.
Cytokine ; 179: 156619, 2024 07.
Article in English | MEDLINE | ID: mdl-38669908

ABSTRACT

Interleukin (IL)-23 is implicated in the pathogenesis of several inflammatory diseases and is usually linked with helper T cell (Th17) biology. However, there is some data linking IL-23 with innate immune biology in such diseases. We therefore examined the effects of IL-23p19 genetic deletion and/or neutralization on in vitro macrophage activation and in an innate immune-driven peritonitis model. We report that endogenous IL-23 was required for maximal macrophage activation by zymosan as determined by pro-inflammatory cytokine production, including a dramatic upregulation of granulocyte-colony stimulating factor (G-CSF). Furthermore, both IL-23p19 genetic deletion and neutralization in zymosan-induced peritonitis (ZIP) led to a specific reduction in the neutrophil numbers, as well as a reduction in the G-CSF levels in exudate fluids. We conclude that endogenous IL-23 can contribute significantly to macrophage activation during an inflammatory response, mostly likely via an autocrine/paracrine mechanism; of note, endogenous IL-23 can directly up-regulate macrophage G-CSF expression, which in turn is likely to contribute to the regulation of IL-23-dependent neutrophil number and function during an inflammatory response, with potential significance for IL-23 targeting particularly in neutrophil-associated inflammatory diseases.


Subject(s)
Inflammation , Interleukin-23 , Myeloid Cells , Neutrophils , Zymosan , Animals , Inflammation/metabolism , Inflammation/immunology , Interleukin-23/metabolism , Mice , Neutrophils/metabolism , Neutrophils/immunology , Myeloid Cells/metabolism , Peritonitis/metabolism , Peritonitis/immunology , Mice, Inbred C57BL , Granulocyte Colony-Stimulating Factor/metabolism , Macrophage Activation , Macrophages/metabolism , Macrophages/immunology , Interleukin-23 Subunit p19/metabolism , Interleukin-23 Subunit p19/genetics , Mice, Knockout
5.
Immunol Cell Biol ; 101(7): 600-609, 2023 08.
Article in English | MEDLINE | ID: mdl-36975092

ABSTRACT

Chemokine (C-C) ligand 17 (CCL17) was first identified as thymus- and activation-regulated chemokine when it was found to be constitutively expressed in the thymus and identified as a T-cell chemokine. This chemoattractant molecule has subsequently been found at elevated levels in a range of autoimmune and inflammatory diseases, as well as in cancer. CCL17 is a C-C chemokine receptor type 4 (CCR4) ligand, with chemokine (C-C) ligand 22 being the other major ligand and, as CCR4 is highly expressed on helper T cells, CCL17 can play a role in T-cell-driven diseases, usually considered to be via its chemotactic activity on T helper 2 cells; however, given that CCR4 is also expressed by other cell types and there is elevated expression of CCL17 in many diseases, a broader CCL17 biology is suggested. In this review, we summarize the biology of CCL17, its regulation and its potential contribution to the pathogenesis of various preclinical models. Reference is made, for example, to recent literature indicating a role for CCL17 in the control of pain as part of a granulocyte macrophage-colony-stimulating factor/CCL17 pathway in lymphocyte-independent models and thus not as a T-cell chemokine. The review also discusses the potential for CCL17 to be a biomarker and a therapeutic target in human disorders.


Subject(s)
Autoimmunity , Receptors, Chemokine , Humans , Ligands , Receptors, Chemokine/metabolism , Chemokine CCL17/metabolism , Chemokines , Inflammation
6.
Osteoarthritis Cartilage ; 31(10): 1327-1341, 2023 10.
Article in English | MEDLINE | ID: mdl-37225052

ABSTRACT

OBJECTIVES: We have previously identified a granulocyte macrophage-colony stimulating factor (GM-CSF)/C-C motif ligand 17 (CCL17) pathway in monocytes/macrophages, in which GM-CSF regulates the formation of CCL17, and it is important for an experimental osteoarthritis (OA) model. We explore here additional OA models, including in the presence of obesity, such as a requirement for this pathway. DESIGN: The roles of GM-CSF, CCL17, CCR4, and CCL22 in various experimental OA models, including those incorporating obesity (eight-week high-fat diet), were investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. Cell populations (flow cytometry) and cytokine messenger RNA (mRNA) expression (qPCR) in knee infrapatellar fat pad were analyzed. Human OA sera were collected for circulating CCL17 levels (ELISA) and OA knee synovial tissue for gene expression (qPCR). RESULTS: We present evidence that: i) GM-CSF, CCL17, and CCR4, but not CCL22, are required for the development of pain-like behavior and optimal disease in three experimental OA models, as well as for exacerbated OA development due to obesity, ii) obesity alone leads to spontaneous knee joint damage in a GM-CSF- and CCL17-dependent manner, and iii) in knee OA patients, early indications are that BMI correlates with a lower Oxford Knee Score (r = -0.458 and p = 0.0096), with elevated circulating CCL17 levels (r = 0.2108 and p = 0.0153) and with elevated GM-CSF and CCL17 gene expression in OA synovial tissue. CONCLUSIONS: The above findings indicate that GM-CSF, CCL17, and CCR4 are involved in obesity-associated OA development, broadening their potential as targets for possible treatments for OA.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor , Osteoarthritis, Knee , Humans , Male , Animals , Mice , Cytokines , Pain , Osteoarthritis, Knee/etiology , Synovial Membrane/metabolism , Chemokine CCL17
7.
Immunity ; 41(1): 14-20, 2014 Jul 17.
Article in English | MEDLINE | ID: mdl-25035950

ABSTRACT

Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature.


Subject(s)
Macrophage Activation/immunology , Macrophages/immunology , Terminology as Topic , Animals , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Guidelines as Topic , Humans , Macrophage Colony-Stimulating Factor/immunology , Mice , Research
8.
J Immunol ; 205(1): 213-222, 2020 07 01.
Article in English | MEDLINE | ID: mdl-32461237

ABSTRACT

It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from Ccl17E/+ reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4+ non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.


Subject(s)
Arthritis, Experimental/immunology , Chemokine CCL17/metabolism , Pain/immunology , Peritonitis/immunology , Pneumonia/immunology , Animals , Arthritis, Experimental/complications , Arthritis, Experimental/pathology , Calcitonin Gene-Related Peptide/metabolism , Chemokine CCL17/genetics , Genes, Reporter/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Mice , Mice, Transgenic , Nerve Growth Factor/metabolism , Pain/diagnosis , Pain/pathology , Pain Measurement , Peritonitis/complications , Peritonitis/pathology , Pneumonia/complications , Pneumonia/pathology , Signal Transduction/immunology , Substance P/metabolism
9.
J Neurosci ; 40(11): 2189-2199, 2020 03 11.
Article in English | MEDLINE | ID: mdl-32019828

ABSTRACT

The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk.SIGNIFICANCE STATEMENT The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.


Subject(s)
Chronic Pain/physiopathology , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Nociceptors/drug effects , Animals , Calcium Signaling/drug effects , Cell Communication , Cells, Cultured , Chronic Pain/chemically induced , Culture Media, Conditioned/pharmacology , Female , Ganglia, Spinal/cytology , Gene Expression Regulation/drug effects , Inflammation/chemically induced , Inflammation/physiopathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Nerve Growth Factor/pharmacology , Nociceptors/physiology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/drug effects , STAT5 Transcription Factor/physiology , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/metabolism , Transcription, Genetic/drug effects
10.
Trends Immunol ; 39(3): 240-255, 2018 03.
Article in English | MEDLINE | ID: mdl-29338939

ABSTRACT

There is burgeoning interest in the interaction between the immune and nervous systems. Pain is mediated by primary sensory neurons (nociceptors) that can respond to a variety of thermal, mechanical and chemical signals. Cytokines are now recognized as important mediators of inflammatory pain. They can induce nociceptor sensitization indirectly via mediators, wherein neurons become primed and thus become more responsive to stimulation; alternatively, there is also evidence that cytokines can directly activate neurons via their specific receptors present on the neuronal cells. We review here the evidence for and against these respective mechanisms, focusing on arthritis and inflammatory skin models. A number of striking inconsistencies amongst the conclusions made in the literature are highlighted and discussed.


Subject(s)
Arthritis/immunology , Cytokines/metabolism , Neurogenic Inflammation/immunology , Nociceptors/physiology , Pain/immunology , Receptors, Cytokine/metabolism , Skin/immunology , Animals , Disease Models, Animal , Humans
11.
J Immunol ; 202(10): 3033-3040, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30988114

ABSTRACT

Studies have demonstrated the importance of a GM-CSF→IFN regulatory factor 4 (IRF4)→CCL17 pathway, first identified in monocytes/macrophages, for arthritic pain and disease development. In this study, we further investigated the involvement of this new pathway in shaping the inflammatory response using the zymosan-induced peritonitis (ZIP) model. ZIP (8 mg of zymosan, i.p., day 0) was induced in C57BL/6 wild-type (WT), GM-CSF-/- , Irf4-/- , and Ccl17E/E mice. In comparison with WT mice, GM-CSF-/- and Irf4-/- mice had a reduced ZIP response, as judged by a reduced number of neutrophils and macrophages in the peritoneal cavity. Moreover, the phenotype of the ZIP macrophages was altered by a lack of GM-CSF or IRF4 (increased IL-10 secretion and Arg1 mRNA expression), with IRF4 levels being lower in GM-CSF-/- ZIP macrophages than in the WT cells. In addition, GM-CSF ̶IRF4 signaling upregulated MHC class II expression in ZIP macrophages and bone marrow-derived macrophages. Although Ccl17 mRNA expression was reduced in ZIP macrophages in the absence of either GM-CSF or IRF4, thus supporting the presence of the new pathway in inflammatory macrophages, CCL17 did not modulate the inflammatory response, both in terms of number of myeloid cells or the macrophage phenotype. Thus, during an inflammatory response, both macrophage numbers and their phenotype can depend on GM-CSF- and IRF4-dependent signaling independently of CCL17.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Interferon Regulatory Factors/immunology , Macrophages/immunology , Signal Transduction/immunology , Animals , Chemokine CCL17/genetics , Chemokine CCL17/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Interferon Regulatory Factors/genetics , Macrophages/pathology , Mice , Mice, Knockout , Signal Transduction/genetics , Up-Regulation/immunology
12.
Epilepsia ; 61(2): 203-215, 2020 02.
Article in English | MEDLINE | ID: mdl-31943156

ABSTRACT

Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti-inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti-inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may be relevant for the pathogenesis of PTE. A major cell type involved in such cascades is the microglial cells-brain-resident immune cells that become activated after brain injury. When activated, these cells can oscillate between different phenotypes, and such polarization states are associated with the release of various pro- and anti-inflammatory mediators that may influence brain repair processes, and also differentially contribute to the development of PTE. As the molecular mechanisms and key signaling molecules associated with microglial polarization in brain are discovered, strategies are now emerging that can modulate this polarization, promoting this as a potential therapeutic strategy for PTE. In this review, we discuss the relevant literature regarding the polarization of brain-resident immune cells following TBI and attempt to put into perspective a role in epilepsy pathogenesis. Finally, we explore potential strategies that could polarize microglia/macrophages toward a neuroprotective phenotype to mitigate PTE development.


Subject(s)
Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/pathology , Epilepsy, Post-Traumatic/etiology , Epilepsy, Post-Traumatic/pathology , Microglia/pathology , Animals , Cell Polarity , Encephalitis/drug therapy , Encephalitis/etiology , Encephalitis/pathology , Epilepsy, Post-Traumatic/therapy , Humans
13.
J Immunol ; 201(7): 2042-2053, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30120124

ABSTRACT

Pain is one of the most debilitating symptoms in many diseases for which there is inadequate management and understanding. CSF-1, also known as M-CSF, acts via its receptor (CSF-1R, c-Fms) to regulate the development of the monocyte/macrophage lineage and to act locally in tissues to control macrophage numbers and function. It has been implicated in the control of neuropathic pain via a central action on microglia. We report in this study that systemic administration of a neutralizing anti-CSF-1R or CSF-1 mAb inhibits the development of inflammatory pain induced by zymosan, GM-CSF, and TNF in mice. This approach also prevented but did not ameliorate the development of arthritic pain and optimal disease driven by the three stimuli in mice, suggesting that CSF-1 may only be relevant when the driving inflammatory insults in tissues are acute and/or periodic. Systemic CSF-1 administration rapidly induced pain and enhanced the arthritis in an inflamed mouse joint, albeit via a different pathway(s) from that used by systemic GM-CSF and TNF. It is concluded that CSF-1 can function peripherally during the generation of inflammatory pain and hence may be a target for such pain and associated disease, including when the clinically important cytokines, TNF and GM-CSF, are involved. Our findings have ramifications for the selection and design of anti-CSF-1R/CSF-1 trials.


Subject(s)
Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Inflammation/immunology , Joints/immunology , Macrophage Colony-Stimulating Factor/metabolism , Macrophages/physiology , Monocytes/physiology , Animals , Antibodies, Neutralizing/administration & dosage , Cell Differentiation , Cell Lineage , Humans , Macrophage Colony-Stimulating Factor/immunology , Mice , Mice, Inbred C57BL , Pain , Receptor, Macrophage Colony-Stimulating Factor/immunology , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Signal Transduction
15.
J Biol Chem ; 293(29): 11415-11423, 2018 07 20.
Article in English | MEDLINE | ID: mdl-29871928

ABSTRACT

Interleukin 4 (IL4) is generally viewed as a Th2 cytokine capable of polarizing macrophages into an anti-inflammatory phenotype, whereas granulocyte macrophage-colony-stimulating factor (GM-CSF) is often viewed as a proinflammatory cytokine with part of this function due to its action on monocytes/macrophages. Paradoxically, these two cytokines act additively to enhance the in vitro differentiation of dendritic cells from precursors such as monocytes. One up-regulated marker of an IL4-polarized M2 macrophage is the chemokine (C-C motif) ligand 17 (CCL17), which we have recently reported to be induced by GM-CSF in monocytes/macrophages in an interferon regulatory factor 4 (IRF4)-dependent manner. In this study, we report that IL4 also induces CCL17 production by acting through IRF4 in human monocytes and murine macrophages. Furthermore, evidence is presented that IL4 up-regulates IRF4 expression at the epigenetic level by enhancing the expression and activity of jumonji domain-containing protein 3 (JMJD3) demethylase. Intriguingly, silencing the signal transducer and activator of transcription 6 (STAT6) gene led to a decrease in not only CCL17 formation, but also in that of its upstream regulators, JMJD3 and IRF4. Moreover, IL4 treatment of human monocytes resulted in an increased association of STAT6 to the promoter regions of the CCL17, IRF4, and JMJD3 genes. Thus, despite their vastly different functions, IL4 and GM-CSF appear to share elements of a common signaling pathway in regulating CCL17 production in human monocytes and murine macrophages.


Subject(s)
Chemokine CCL17/genetics , Epigenesis, Genetic , Interleukin-4/genetics , Macrophages/metabolism , Monocytes/metabolism , Transcriptional Activation , Animals , Cells, Cultured , Humans , Interferon Regulatory Factors/genetics , Jumonji Domain-Containing Histone Demethylases/genetics , Mice , Mice, Inbred C57BL , Up-Regulation
16.
J Immunol ; 198(9): 3565-3575, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28320832

ABSTRACT

G-CSF or CSF-3, originally defined as a regulator of granulocyte lineage development via its cell surface receptor (G-CSFR), can play a role in inflammation, and hence in many pathologies, due to its effects on mature lineage populations. Given this, and because pain is an extremely important arthritis symptom, the efficacy of an anti-G-CSFR mAb for arthritic pain and disease was compared with that of a neutrophil-depleting mAb, anti-Ly6G, in both adaptive and innate immune-mediated murine models. Pain and disease were ameliorated in Ag-induced arthritis, zymosan-induced arthritis, and methylated BSA/IL-1 arthritis by both prophylactic and therapeutic anti-G-CSFR mAb treatment, whereas only prophylactic anti-Ly6G mAb treatment was effective. Efficacy for pain and disease correlated with reduced joint neutrophil numbers and, importantly, benefits were noted without necessarily the concomitant reduction in circulating neutrophils. Anti-G-CSFR mAb also suppressed zymosan-induced inflammatory pain. A new G-CSF-driven (methylated BSA/G-CSF) arthritis model was established enabling us to demonstrate that pain was blocked by a cyclooxygenase-2 inhibitor, suggesting an indirect effect on neurons. Correspondingly, dorsal root ganglion neurons cultured in G-CSF failed to respond to G-CSF in vitro, and Csf3r gene expression could not be detected in dorsal root ganglion neurons by single-cell RT-PCR. These data suggest that G-CSFR/G-CSF targeting may be a safe therapeutic strategy for arthritis and other inflammatory conditions, particularly those in which pain is important, as well as for inflammatory pain per se.


Subject(s)
Antibodies, Blocking/therapeutic use , Arthritis, Experimental/therapy , Arthritis, Rheumatoid/therapy , Immunotherapy/methods , Neurons/drug effects , Neutrophils/immunology , Receptors, Granulocyte Colony-Stimulating Factor/metabolism , Animals , Antigens, Ly/immunology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Cells, Cultured , Disease Models, Animal , Granulocyte Colony-Stimulating Factor/metabolism , Humans , Leukocyte Reduction Procedures , Mice , Mice, Inbred C57BL , Neurons/physiology , Neutrophils/drug effects , Neutrophils/pathology , Pain Management , Receptors, Granulocyte Colony-Stimulating Factor/genetics , Receptors, Granulocyte Colony-Stimulating Factor/immunology
17.
J Immunol ; 196(5): 2230-8, 2016 Mar 01.
Article in English | MEDLINE | ID: mdl-26819203

ABSTRACT

IFN regulatory factors (IRFs) help to shape the immune response to pathogens by imparting signaling specificity to individual TLRs. We recently demonstrated that IRF6 provides specificity to TLR2 signaling in oral epithelial cells. TLR2 plays an important role in eliciting inflammation to Porphyromonas gingivalis, a keystone pathogen in periodontitis. Therefore, we investigated a role for IRF6 in mediating the inflammatory cytokine response of oral epithelial cells to P. gingivalis. IRF6 expression was strongly upregulated when human oral epithelial cells were challenged with P. gingivalis. Moreover, gene silencing and gene promoter experiments indicated that IRF6 acts downstream of IL-1R-associated kinase 1 to stimulate the expression of the IL-1 family cytokine IL-36γ in response to P. gingivalis. IRF6 and IL-1R-associated kinase 1 also regulated the stimulation of IL-36γ expression by a TLR2 agonist. IL-36γ was shown to elicit inflammatory responses by human monocyte-derived dendritic cells and macrophages, including the expression of the neutrophil chemokines IL-8 and CXCL1, as well as the Th17 chemokine CCL20. IL-36γ similarly stimulated their expression by human oral epithelial cells. Significantly, the Th17 cytokine IL-17 not only stimulated the expression of important regulators of neutrophil recruitment and survival by oral epithelial cells, but IL-17 also stimulated them to express IL-36γ. Thus, our findings suggest that IRF6 is likely to promote inflammation to P. gingivalis through its regulation of IL-36γ.


Subject(s)
Gene Expression Regulation , Interferon Regulatory Factors/metabolism , Interleukin-1/genetics , Mouth Mucosa/metabolism , Mouth Mucosa/virology , Porphyromonas gingivalis/immunology , Bacteroidaceae Infections/genetics , Bacteroidaceae Infections/immunology , Bacteroidaceae Infections/microbiology , Cells, Cultured , Dendritic Cells/immunology , Dendritic Cells/metabolism , Epithelial Cells , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Inflammation/microbiology , Interleukin-1 Receptor-Associated Kinases/metabolism , Interleukin-17/metabolism , Macrophages/immunology , Macrophages/metabolism , Models, Biological , Mouth Mucosa/immunology , Toll-Like Receptor 2/metabolism , Up-Regulation
18.
Eur J Immunol ; 46(5): 1235-45, 2016 05.
Article in English | MEDLINE | ID: mdl-26848119

ABSTRACT

Neutrophils are an abundant cell type in many chronic inflammatory diseases such as rheumatoid arthritis (RA); however, their contribution to the pathology of RA has not been widely studied. A key cytokine involved in neutrophil development and function is granulocyte-colony stimulating factor (G-CSF). In this study we used the K/BxN serum-transfer arthritis (STA) model, mimicking the effector phase of RA, to investigate the importance of G-CSF in arthritis development and its relation to neutrophils. Here, we show for the first time in this model that G-CSF levels are increased both in the serum and in inflamed paws of arthritic mice and importantly that G-CSF blockade leads to a profound reduction in arthritis severity, as well as reduced numbers of neutrophils in blood. Moreover, CXCL1 and CXCL2 levels in the arthritic joints were also lowered. Our data demonstrate that G-CSF is a pivotal driver of the disease progression in the K/BxN STA model and possibly acts in part by regulating neutrophil numbers in the circulation. Therefore, our findings suggest that G-CSF might be a suitable target in RA, and perhaps in other immune complex-driven pathologies.


Subject(s)
Antigen-Antibody Complex/immunology , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/physiopathology , Granulocyte Colony-Stimulating Factor/immunology , Animals , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/etiology , Chemokine CXCL1/immunology , Chemokine CXCL2/immunology , Disease Models, Animal , Disease Progression , Granulocyte Colony-Stimulating Factor/blood , Humans , Joints/immunology , Mice , Neutrophils/immunology
19.
Eur J Immunol ; 46(4): 952-63, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26786702

ABSTRACT

Osteoclast-associated receptor (OSCAR) is an activating receptor expressed by human myeloid cells. Collagen type I (ColI) and collagen type II (ColII) serve as ligands for OSCAR. OSCAR-collagen interaction stimulates RANK-dependent osteoclastogenesis. We have recently reported that OSCAR promotes functional maturation of monocyte-derived dendritic cells. OSCAR is upregulated on monocytes from rheumatoid arthritis (RA) patients with active disease, and these monocytes show an increased proosteoclastogenic potential. In the current study, we have addressed a functional role for an OSCAR-collagen interaction on monocytes. We show that OSCAR-ColII signaling promoted the survival of monocytes. Moreover, ColII stimulated the release of proinflammatory cytokines by monocytes from healthy donors, which could be completely blocked by an anti-OSCAR monoclonal antibody. Mononuclear cells from the synovial fluid of RA patients plated on ColII secreted TNF-α and IL-8 in an OSCAR-dependent manner. Global RNA profiling showed that components of multiple signaling pathways relevant to RA pathogenesis are regulated at the transcriptional level by OSCAR in monocytes. Thus, OSCAR can play a proinflammatory role in monocyte-derived cells and may contribute crucially on multiple levels to RA pathogenesis.


Subject(s)
Arthritis, Rheumatoid/pathology , Collagen Type II/metabolism , Inflammation/immunology , Monocytes/immunology , Receptors, Cell Surface/metabolism , Antibodies, Monoclonal/immunology , Arthritis, Rheumatoid/immunology , Cell Differentiation/immunology , Cells, Cultured , Collagen Type I/metabolism , Dendritic Cells/immunology , Humans , Inflammation Mediators/metabolism , Interleukin-8/metabolism , Osteoclasts/cytology , Signal Transduction/immunology , Synovial Fluid/cytology , Tumor Necrosis Factor-alpha/metabolism
20.
J Immunol ; 195(1): 134-44, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-26019271

ABSTRACT

M-CSF (or CSF-1) and GM-CSF can regulate the development and function of the mononuclear phagocyte system (MPS). To address some of the outstanding and sometimes conflicting issues surrounding this biology, we undertook a comparative analysis of the effects of neutralizing mAbs to these CSFs on murine MPS populations in the steady-state and during acute inflammatory reactions. CSF-1 neutralization, but not of GM-CSF, in normal mice rapidly reduced the numbers of more mature Ly6C(-) monocytes in blood and bone marrow, without any effect on proliferating precursors, and also the numbers of the resident peritoneal macrophages, observations consistent with CSF-1 signaling being essential only at a relatively late state in steady-state MPS development; in contrast, GM-CSF neutralization had no effect on the numbers of these particular populations. In Ag-induced peritonitis (AIP), thioglycolate-induced peritonitis, and LPS-induced lung inflammation, CSF-1 neutralization lowered inflammatory macrophage number; in the AIP model, this reduced number was not due to suppressed proliferation. More detailed studies with the convenient AIP model indicated that CSF-1 neutralization led to a relatively uniform reduction in all inflammatory cell populations; GM-CSF neutralization, in contrast, was more selective, resulting in the preferential loss among the MPS populations of a cycling, monocyte-derived inflammatory dendritic cell population. Some mechanistic options for the specific CSF-dependent biologies enumerated are discussed.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Macrophage Colony-Stimulating Factor/immunology , Macrophages/immunology , Monocytes/immunology , Peritonitis/immunology , Pneumonia/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Antigens, Ly/genetics , Antigens, Ly/immunology , Cell Count , Cytokines/genetics , Cytokines/immunology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/pathology , Gene Expression Regulation , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Lipopolysaccharides , Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Macrophage Colony-Stimulating Factor/genetics , Macrophages/drug effects , Macrophages/pathology , Mice , Monocytes/drug effects , Monocytes/pathology , Peritonitis/chemically induced , Peritonitis/genetics , Peritonitis/pathology , Pneumonia/chemically induced , Pneumonia/genetics , Pneumonia/pathology , Primary Cell Culture , Receptors, CCR7/genetics , Receptors, CCR7/immunology , Signal Transduction , Thioglycolates , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/immunology
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