Showing papers in "Journal of Leukocyte Biology in 2009"
TL;DR: The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes, which makes TAM an attractive target of novel biological therapies of tumors.
Abstract: The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes TAM, major players in the connection between inflammation and cancer, summarize a number of functions (eg, promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors
1,225 citations
TL;DR: S 100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread.
Abstract: The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin-induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.
714 citations
TL;DR: It is proposed that HSPs are molecular chaperones that bind protein and nonprotein molecules with exposed hydrophobic residues including lipid‐based TLR ligands to MHC class I molecules at the cell surface for presentation to lymphocytes.
Abstract: Heat shock proteins (HSPs) such as HSP 60 (Hsp60), Hsp70, Hsp90, and gp96, have been reported to play important roles in antigen presentation and cross-presentation, activation of macrophages and lymphocytes, and activation and maturation of dendritic cells. HSPs contain peptide-binding domains that bind exposed hydrophobic residues of substrate proteins. As part of their molecular chaperone functions, HSPs bind and deliver chaperoned, antigenic peptides to MHC class I molecules at the cell surface for presentation to lymphocytes. HSPs also bind nonprotein molecules with exposed hydrophobic residues including lipid-based TLR ligands. Recombinant HSP products may be contaminated with pathogen-associated molecules that contain exposed hydrophobic residues such as LPS (a TLR4 ligand), lipoprotein (a TLR2 ligand), and flagellin (a TLR5 ligand). These contaminants appear to be responsible for most, if not all, reported in vitro cytokine effects of HSPs, as highly purified HSPs do not show any cytokine effects. We propose that HSPs are molecular chaperones that bind protein and nonprotein molecules with exposed hydrophobic residues. The reported antigen presentation and cross-presentation and in vitro HSP cytokine functions are a result of molecules bound to or chaperoned by HSPs but not a result of HSPs themselves.
430 citations
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TL;DR: HMGB1 has dual activities, solo or in company; it is speculated that this may serve the body’s necessity to sacrifice or reconstruct tissues as required by the presence or absence of pathogens.
Abstract: HMGB1, outside of a cell, is a trigger of inflammation and a stimulus for tissue reconstruction; the balance may depend on the complexes it forms with other molecules. HMGB1 is the prime example of a danger signal that originates from the damaged self rather than from invading pathogens. HMGB1 is released by cells that die traumatically and is secreted by cells destined to die and by activated cells of the innate immunity system. As a danger signal, HMGB1 is expected to trigger inflammation, but recent reports indicate that pure recombinant HMGB1 has no proinflammatory activity and only acts as a chemoattractant and a mitogen. However, HMGB1 forms highly inflammatory complexes with ssDNA, LPS, IL-1beta, and nucleosomes, which interact with TLR9, TLR4, IL-1R, and TLR2 receptors, respectively. Thus, HMGB1 has dual activities, solo or in company; I speculate that this may serve our body's necessity to sacrifice or reconstruct tissues as required by the presence or absence of pathogens.
402 citations
TL;DR: The differential distribution of NK and NKT cells in mouse, rat, and human livers, the ultrastructural similarities and differences between liver NK andNKT cells, and the regulation of liverNK and N KT cells in a variety of murine liver injury models are discussed.
Abstract: Hepatic lymphocytes are enriched in NK and NKT cells that play important roles in antiviral and antitumor defenses and in the pathogenesis of chronic liver disease. In this review, we discuss the differential distribution of NK and NKT cells in mouse, rat, and human livers, the ultrastructural similarities and differences between liver NK and NKT cells, and the regulation of liver NK and NKT cells in a variety of murine liver injury models. We also summarize recent findings about the role of NK and NKT cells in liver injury, fibrosis, and repair. In general, NK and NKT cells accelerate liver injury by producing proinflammatory cytokines and killing hepatocytes. NK cells inhibit liver fibrosis via killing early-activated and senescent-activated stellate cells and producing IFN-γ. In regulating liver fibrosis, NKT cells appear to be less important than NK cells as a result of hepatic NKT cell tolerance. NK cells inhibit liver regeneration by producing IFN-γ and killing hepatocytes; however, the role of NK cells on the proliferation of liver progenitor cells and the role of NKT cells in liver regeneration have been controversial. The emerging roles of NK/NKT cells in chronic human liver disease will also be discussed. Understanding the role of NK and NKT cells in the pathogenesis of chronic liver disease may help us design better therapies to treat patients with this disease.
351 citations
TL;DR: This review about microglia aims to introduce the reader extensively into their ontogeny, cell biology, and involvement in different neuropathologies.
Abstract: Microglia are perhaps the most underestimated cell type of our immune system. Not only were immunologists unaware of their capabilities until recently, but also, some neuroscientists denied their actual existence until the late 20th century. Nowadays, their presence is confirmed extensively, as demonstrated by numerous reports describing their involvement in virtually all neuropathologies. However, despite distinct approaches, their origin remains a point of controversy. Although many agree about their myeloid-monocytic ancestry, the precise progenitor cells and the differentiation mechanisms, which give rise to microglia in the different developmental stages of the CNS, are not unraveled yet. Mostly, this can be attributed to their versatile phenotype. Indeed, microglia show a high morphological plasticity, which is related to their functional state. This review about microglia aims to introduce the reader extensively into their ontogeny, cell biology, and involvement in different neuropathologies.
319 citations
TL;DR: HMGB1 acts broadly with many but not all immunostimulatory molecules to amplify their activity in a synergistic manner and cannot induce detectable IL‐6 production on its own.
Abstract: The nuclear protein HMGB1 has previously been demonstrated to act as an alarmin and to promote inflammation upon extracellular release, yet its mode of action is still not well defined. Access to highly purified HMGB1 preparations from prokaryotic and eukaryotic sources enabled studies of activation of human PBMC or synovial fibroblast cultures in response to HMGB1 alone or after binding to cofactors. HMGB1 on its own could not induce detectable IL-6 production. However, strong enhancing effects on induction of proinflammatory cytokine production occurred when the protein associated with each of the separate proinflammatory molecules, rhIL-1beta, the TLR4 ligand LPS, the TLR9 ligand CpG-ODN, or the TLR1-TLR2 ligand Pam3CSK4. The bioactivities were recorded in cocultures with preformed HMGB1 complexes but not after sequential or simultaneous addition of HMGB1 and the individual ligands. Individual A-box and B-box domains of HMGB1 had the ability to bind LPS and enhance IL-6 production. Heat denaturation of HMGB1 eliminated this enhancement. Cocultures with HMGB1 and other proinflammatory molecules such as TNF, RANKL, or IL-18 did not induce enhancement. HMGB1 thus acts broadly with many but not all immunostimulatory molecules to amplify their activity in a synergistic manner.
301 citations
TL;DR: A hypothetical model in which sustained PI3K activity at the membrane limits the availability of thePI3K substrate, thereby negatively regulating signaling is proposed, which would negatively regulate signaling.
Abstract: TLRs activate immune responses by sensing microbial structures such as bacterial LPS, viral RNA, and endogenous "danger" molecules released by damaged host cells. MyD88 is an adapter protein that mediates signal transduction for most TLRs and leads to activation of NF-kappaB and MAPKs and production of proinflammatory cytokines. TLR4-mediated signaling also leads to rapid activation of PI3K, one of a family of kinases involved in regulation of cell growth, apoptosis, and motility. LPS stimulates phosphorylation of Akt, a downstream target of PI3K, in wild-type (WT) mouse macrophages. LPS-induced phosphorylation of Akt serine 473 was blunted in MyD88(-/-) macrophages and was completely TLR4-dependent. MyD88 and p85 were shown previously to co-immunoprecipitate, and a YXXM motif within the Toll-IL-1 resistance (TIR) domain of MyD88 was suggested to be important for this interaction. To test this hypothesis, we compared expressed MyD88 variants with mutations within the YXXM motif or lacking the TIR domain or death domain and measured their capacities to bind PI3K p85, MyD88, and TLR4 by co-immunoprecipitation analyses. The YXXM --> YXXA mutant MyD88 bound more strongly to p85, TLR4, and WT MyD88 than the other variants, yet was significantly less active than WT MyD88, suggesting that sustained interaction of MyD88/PI3K with the TLR4 intracellular "signaling platform" negatively regulates signaling. We propose a hypothetical model in which sustained PI3K activity at the membrane limits the availability of the PI3K substrate, thereby negatively regulating signaling.
287 citations
TL;DR: Findings demonstrate that constitutive and LPS‐induced type I IFN play significant roles in regulating the differences in phenotype and function between BMM and GM‐BMM.
Abstract: M-CSF and GM-CSF are mediators involved in regulating the numbers and function of macrophage lineage populations and have been shown to contribute to macrophage heterogeneity. Type I IFN is an important mediator produced by macrophages and can have profound regulatory effects on their properties. In this study, we compared bone marrow-derived macrophages (BMM) and GM-CSF-induced BMM (GM-BMM) from wild-type and IFNAR1(-/-) mice to assess the contribution of endogenous type I IFN to the phenotypic differences between BMM and GM-BMM. BMM were capable of higher constitutive IFN-beta production, which contributed significantly to their basal transcriptome. Microarray analysis found that of the endogenous type I IFN-regulated genes specific to either BMM or GM-BMM, 488 of these gene alterations were unique to BMM, while only 50 were unique to GM-BMM. Moreover, BMM displayed enhanced basal mRNA levels, relative to GM-BMM, of a number of genes identified as being dependent on type I IFN signaling, including Stat1, Stat2, Irf7, Ccl5, Ccl12, and Cxcl10. As a result of prior type I IFN "priming," upon LPS stimulation BMM displayed increased activation of the MyD88-independent IRF-3/STAT1 pathways compared with GM-BMM, which correlated with the distinct cytokine/chemokine profiles of the two macrophage subsets. Furthermore, the autocrine type I IFN signaling loop regulated the production of the M1 and M2 signature cytokines, IL-12p70 and IL-10. Collectively, these findings demonstrate that constitutive and LPS-induced type I IFN play significant roles in regulating the differences in phenotype and function between BMM and GM-BMM.
281 citations
TL;DR: An overview of these complex interactions between selectins and their ligands, and the integrins binding to Ig‐like cell adhesion molecules as well as to GP, present in the extracellular matrix or on activated endothelium are provided.
Abstract: Platelets, monocytes, and endothelial cells are instrumental in the development and progression of cardiovascular diseases. Inflammation, a key process underlying cardiovascular disorders, is accompanied and amplified by activation of platelets and consequent binding of such platelets to the endothelium. There, platelet-derived chemokines, in conjunction with increased expression of adhesion molecules, promote the recruitment of circulating monocytes that will eventually migrate across the endothelial lining of the vessel into the tissues. Additionally, platelets may already become activated in the circulation and may form platelet-monocyte complexes, which show increased adhesive and migratory capacities themselves but also facilitate recruitment of noncomplexed leukocytes. They should therefore be considered as important mediators of inflammation. In molecular terms, these events are additionally governed by chemokines released and presented by the endothelium as well as the different classes of endothelial adhesion molecules that regulate the interactions among the various cell types. Most important in this respect are the selectins and their ligands, such as P-selectin glycoprotein (GP) ligand 1, and the integrins binding to Ig-like cell adhesion molecules as well as to GP, such as von Willebrand factor, present in the extracellular matrix or on activated endothelium. This review aims to provide an overview of these complex interactions and of their functional implications for inflammation and development of cardiovascular disease.
281 citations
TL;DR: Monitoring of plasma sRAGE levels may provide a novel biomarker platform for tracking chronic inflammatory diseases, their severity, and response to therapeutic intervention.
Abstract: The RAGE binds multiple ligand families linked to hyperglycemia, aging, inflammation, neurodegeneration, and cancer. Activation of RAGE by its ligands stimulates diverse signaling cascades. The recent observation that the cytoplasmic domain of RAGE interacts with diaphanous or mDia-1 links RAGE signal transduction to cellular migration and activation of the Rho GTPases, cdc42 and rac-1. Pharmacological blockade of RAGE or genetic deletion of RAGE imparts significant protection in murine models of diabetes, inflammatory conditions, Alzheimer’s disease, and tumors. Intriguingly, soluble forms of RAGE, including the splice variant-derived esRAGE, circulate in human plasma. Studies in human subjects suggest that sRAGE levels may be modulated by the diseases impacted by RAGE and its ligands. Thus, in addition to being a potential therapeutic target in chronic disease, monitoring of plasma sRAGE levels may provide a novel biomarker platform for tracking chronic inflammatory diseases, their severity, and response to therapeutic intervention. J. Leukoc. Biol. 86: 505–512; 2009.
TL;DR: Major constraints associated with a trip to Mars are summarized, immunological hazards associated with this type of mission are presented, and it is shown that current understanding of the immunosuppressive effects of spaceflight is limited.
Abstract: This year, we celebrate the 40th birthday of the first landing of humans on the moon. By 2020, astronauts should return to the lunar surface and establish an outpost there that will provide a technical basis for future manned missions to Mars. This paper summarizes major constraints associated with a trip to Mars, presents immunological hazards associated with this type of mission, and shows that our current understanding of the immunosuppressive effects of spaceflight is limited. Weakening of the immune system associated with spaceflight is therefore an area that should be considered more thoroughly before we undertake prolonged space voyages.
TL;DR: The literature examining CXCR1 and CX CR2 in PMN function during human and modeled diseases will be reviewed, asking whether the functional differences can be perceived based on alterations in the role PMN play in these processes.
Abstract: PMN are critical to innate immunity and are fundamental to antibacterial defense. To localize to sites of infection, PMN possess receptors that detect chemoattractant stimuli elicited at the site, such as chemokines, complement split products, or bioactive lipids. Signaling through these receptors stimulates chemotaxis toward the site of infection but also activates a number of biochemical processes, with the result that PMN kill invading bacteria. PMN possess two receptors, CXCR1 and CXCR2, for the N-terminal ELR motif-containing CXC chemokines, although only two chemokine members bind both receptors and the remainder binding only CXCR2. This peculiar pattern in receptor specificity has drawn considerable interest and investigation into whether signaling through each receptor might impart unique properties on the PMN. Indeed, at first glance, CXCR1 and CXCR2 appear to be functionally redundant; however, there are differences. Considering these proinflammatory activities of activating PMN through chemokine receptors, there has been great interest in the possibility that blocking CXCR1 and CXCR2 on PMN will provide a therapeutic benefit. The literature examining CXCR1 and CXCR2 in PMN function during human and modeled diseases will be reviewed, asking whether the functional differences can be perceived based on alterations in the role PMN play in these processes.
TL;DR: CD8+IL‐17+ T cells share some key features with Th17 cells and exhibit remarkable differential abilities attributable to the CD8+ lineage of T lymphocytes, adding new insights into the functional resources of IL‐17‐producing cells from human epidermis that could be of potential interest to the understanding of the pathogenesis of psoriasis.
Abstract: IL-17-producing CD4+ T lymphocytes (Th17) are currently considered relevant participants in the pathogenesis of psoriasis skin lesions. However, little is known about the potential role of IL-17-producing CD8+ T cells, which are also present at the psoriatic plaque. We have addressed the functional characterization of this CD8+ subtype of T lymphocytes from psoriasis patients. Our results show that CD8+IL-17+ cells from psoriasis-inflamed skin tissue produce TNF-alpha and IFN-gamma (Th1-related cytokines) as well as IL-17, IL-21, and IL-22 (Th17-related cytokines) efficiently. A significant up-regulation of the RORC transcription factor is also observed. These cells are refractory to Tregs but show a proliferative response to anti-CD3/CD28 stimulation that is enhanced by IL-12 and IL-15. Blocking of TNF-alpha activity inhibits TCR-mediated activation and IL-17 production. CD8+IL-17+ T cells are cytotoxic cells that display TCR/CD3-mediated cytotoxic abilities to kill target cells. Thus, CD8+IL-17+ T cells share some key features with Th17 cells and exhibit remarkable differential abilities attributable to the CD8+ lineage of T lymphocytes, adding new insights into the functional resources of IL-17-producing cells from human epidermis that could be of potential interest to our understanding of the pathogenesis of psoriasis.
TL;DR: It is demonstrated that myeloid‐derived suppressor cells are an intermediary through which inflammation promotes type 2 immune responses, and they identify the TLR4 pathway in MDSC as a potential target for down‐regulating immune suppression and promoting anti‐tumor immunity.
Abstract: Myeloid-derived suppressor cells (MDSC) are potent inhibitors of anti-tumor immunity that facilitate tumor progression by blocking the activation of CD4+ and CD8+ T cells and by promoting a type 2 immune response through their production of IL-10 and down-regulation of macrophage production of IL-12. MDSC accumulate in many cancer patients and are a significant impediment to active cancer immunotherapies. Chronic inflammation has been shown recently to enhance the accumulation of MDSC and to increase their suppression of T cells. These findings led us to hypothesize that inflammation contributes to tumor progression through the induction of MDSC, which create a favorable environment for tumor growth. As chronic inflammation also drives type 2 immune responses, which favor tumor growth, we asked if inflammation mediates this effect through MDSC. We find that IL-1β-induced inflammation increased IL-10 production by MDSC and induces MDSC, which are more effective at down-regulating macrophage production of IL-12 as compared with MDSC isolated from less-inflammatory tumor microenvironments, thereby skewing tumor immunity toward a type 2 response. Inflammation heightens MDSC phenotype by signaling through the TLR4 pathway and involves up-regulation of CD14. Although this pathway is well-recognized in other myeloid cells, it has not been implicated previously in MDSC function. These studies demonstrate that MDSC are an intermediary through which inflammation promotes type 2 immune responses, and they identify the TLR4 pathway in MDSC as a potential target for down-regulating immune suppression and promoting anti-tumor immunity.
TL;DR: The current understanding of MAPK function in the regulation of hematopoiesis in general and myelopoiedis in particular is summarized and the consequences of aberrant MAPK activation in the pathogenesis of various myeloid malignancies will be discussed.
Abstract: The MAPKs are a family of serine/threonine kinases that play an essential role in connecting cell-surface receptors to changes in transcriptional programs. MAPKs are part of a three-component kinase module consisting of a MAPK, an upstream MEK, and a MEKK that couples the signals from cell-surface receptors to trigger downstream pathways. Three major groups of MAPKs have been characterized in mammals, including ERKs, JNKs, and p38MAPKs. Over the last decade, extensive work has established that these proteins play critical roles in the regulation of a wide variety of cellular processes including cell growth, migration, proliferation, differentiation, and survival. It has been demonstrated that ERK, JNK, and p38MAPK activity can be regulated in response to a plethora of hematopoietic cytokines and growth factors that play critical roles in hematopoiesis. In this review, we summarize the current understanding of MAPK function in the regulation of hematopoiesis in general and myelopoiesis in particular. In addition, the consequences of aberrant MAPK activation in the pathogenesis of various myeloid malignancies will be discussed.
TL;DR: The polarization of macrophages dramatically skews the secretion of high mobility group box 1 (HMGB1), TNF‐α, vascular endothelial growth factor, and metalloproteinase 9 (MMP‐9), molecules involved in the regulation of cell diapedesis and migration, and demonstrates their ability to attract stem cells, which is conserved throughout their polarization.
Abstract: Inflammatory macrophages recruited at the site of damaged muscles progressively acquire an alternative activation profile. Inflammatory (M1) and alternatively activated (M2) macrophages exert various and even opposite functions. M1 cells amplify tissue damage, and M2 cells dispose of necrotic fibers and deliver survival signals to myogenic precursors, finally supporting healing. A critical step in muscle healing is the recruitment of myogenic stem cells, including vessel-associated stem cells (mesoangioblasts), which have been demonstrated to home to damaged skeletal muscle selectively and preferentially. Little information is available about the signals involved and the role played by infiltrating macrophages. Here, we report that the polarization of macrophages dramatically skews the secretion of high mobility group box 1 (HMGB1), TNF-alpha, vascular endothelial growth factor, and metalloproteinase 9 (MMP-9), molecules involved in the regulation of cell diapedesis and migration. All polarized macrophage populations were strikingly effective at inducing mesoangioblast migration. By means of specific inhibitors, we verified that the recruitment of mesoangioblasts requires the secretion of HMGB1 and TNF-alpha by M1 cells and of MMP-9 by M2 cells. Together, these data demonstrate a feature, unrecognized previously, of macrophages: their ability to attract stem cells, which is conserved throughout their polarization. Moreover, they open the possibility of novel strategies, aimed at interfering selectively with signals that recruit blood-derived stem cells toward pro- or anti-inflammatory macrophages.
TL;DR: Recent findings about the biology of IFN‐λs and their pathophysiological roles in viral infection, cancer, and immune responses of the innate and adaptive arms are summarized.
Abstract: IFN-s, including IFN-1, IFN-2, and IFN-3, also known as IL-29, IL-28A, or IL-28B, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. The IFN-R complex consists of a unique ligand-binding chain, IFN-R1 (also designated IL-28R), and an accessory chain, IL-10R2, which is shared with receptors for IL-10-related cytokines. IFN-s signal through the IFN-R and activate pathways of JAK-STATs and MAPKs to induce antiviral, antiproliferative, antitumor, and immune responses. In this review, we summarize recent findings about the biology of IFN-s and their pathophysiological roles in viral infection, cancer, and immune responses of the innate and adaptive arms. J. Leukoc. Biol. 86: 23–32; 2009.
TL;DR: New insights into the molecular mechanisms of defective efferocytosis in advanced atheromata may open the way for novel therapeutic strategies for atherothrombotic vascular disease, the leading cause of death in the industrialized world.
Abstract: Throughout atherosclerotic lesion development, intimal macrophages undergo apoptosis, a form of death that usually prevents cellular necrosis. In advanced atherosclerotic lesions, however, these apoptotic macrophages become secondarily necrotic and coalesce over time into a key feature of vulnerable plaques, the necrotic core. This event is critically important, as necrotic core formation in these advanced atheromata is thought to promote plaque disruption and ultimately, acute atherothrombotic vascular disease. Increasing evidence suggests that the mechanism behind postapoptotic macrophage necrosis in advanced atherosclerosis is defective phagocytic clearance or "efferocytosis" of the apoptotic cells. Thus, understanding the cellular and molecular mechanisms of efferocytosis in atherosclerosis and why efferocytosis becomes defective in advanced lesions is an important goal. Molecular-genetic causation studies in mouse models of advanced atherosclerosis have provided evidence that several molecules known to be involved in efferocytosis, including TG2, MFG-E8, complement C1q, Mertk, lysoPC, and Fas, play important roles in the clearance of apoptotic cells in advanced plaques. These and future insights into the molecular mechanisms of defective efferocytosis in advanced atheromata may open the way for novel therapeutic strategies for atherothrombotic vascular disease, the leading cause of death in the industrialized world.
TL;DR: Data is presented supporting the critical role fibrocytes play in the pathogenesis of pulmonary fibrosis and the role these cells play in promoting the deposition of ECM.
Abstract: Pulmonary fibrosis is associated with a number of disorders that affect the lung. Although there are several cellular types that are involved in the pathogenesis pulmonary fibrosis, the resident lung fibroblast has been viewed traditionally as the primary cell involved in promoting the deposition of ECM that culminates in pulmonary fibrosis. However, recent findings demonstrate that a circulating cell (i.e., the fibrocyte) can contribute to the evolution of pulmonary fibrosis. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of cell-surface markers related to leukocytes, hematopoietic progenitor cells, and fibroblasts. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. In this review, we present data supporting the critical role these cells play in the pathogenesis of pulmonary fibrosis.
TL;DR: Zinc at low concentrations, through inhibition of CN, sustains phosphorylation of the transcription factor CREB, yielding greater IFN‐γ expression in T cells, suggesting that ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN-γ regulation in T Cells.
Abstract: The zinc transporter ZIP8 is highly expressed in T cells derived from human subjects. T cell ZIP8 expression was markedly up-regulated upon in vitro activation. T cells collected from human subjects who had received oral zinc supplementation (15 mg/day) had higher expression of the activation marker IFN-γ upon in vitro activation, indicating a potentiating effect of zinc on T cell activation. Similarly, in vitro zinc treatment of T cells along with activation resulted in increased IFN-γ expression with a maximum effect at 3.1 μM. Knockdown of ZIP8 in T cells by siRNA decreased ZIP8 levels in nonactivated and activated cells and concomitantly reduced secretion of IFN-γ and perforin, both signatures of activation. Overexpression of ZIP8 by transient transfection caused T cells to exhibit enhanced activation. Confocal microscopy established that ZIP8 is localized to the lysosome where ZIP8 abundance is increased upon activation. Loss of lysosomal labile zinc in response to activation was measured by flow cytometry using a zinc fluorophore. Zinc between 0.8 and 3.1 μM reduced CN phosphatase activity. CN was also inhibited by the CN inhibitor FK506 and ZIP8 overexpression. The results suggest that zinc at low concentrations, through inhibition of CN, sustains phosphorylation of the transcription factor CREB, yielding greater IFN-γ expression in T cells. ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN-γ regulation in T cells.
TL;DR: This review will discuss the role of innate immune cells following IAV infection, with a particular focus on DC and their ability to induce and regulate the adaptive IAV‐specific immune response.
Abstract: Adaptive immune responses are critical for the control and clearance of influenza A virus (IAV) infection. However, in recent years, it has become increasingly apparent that innate immune cells, including natural killer cells, alveolar macrophages (aMφ), and dendritic cells (DC) are essential following IAV infection in the direct control of viral replication or in the induction and regulation of virus-specific adaptive immune responses. This review will discuss the role of these innate immune cells following IAV infection, with a particular focus on DC and their ability to induce and regulate the adaptive IAV-specific immune response.
TL;DR: In support of the functional plasticity hypothesis, administration of slow‐release microsphere‐encapsulated IL‐12 successfully reprogrammed TAMφs in situ, reducing Mφ support of tumor growth and metastasis and enhancing M φ proimmunogenic activities.
Abstract: The extent to which the functional heterogeneity of Mϕs is dependent on the differentiation of functional sublineages remains unresolved. One alternative hypothesis proposes that Mϕs are functionally plastic cells, which are capable of altering their functional activities progressively in response to progressively changing signaling molecules generated in their microenvironment. This “functional plasticity” hypothesis predicts that the functionally polarized Mϕs in chronic pathologies do not represent Mϕ sublineages but rather, are mutable phenotypes sustained by chronic signaling from the pathological environment. Solid TAMϕs are chronically polarized to provide activities that support tumor growth and metastasis and suppress adaptive immune responses. In support of the functional plasticity hypothesis, administration of slow-release microsphere-encapsulated IL-12 successfully reprogrammed TAMϕs in situ, reducing Mϕ support of tumor growth and metastasis and enhancing Mϕ proimmunogenic activities. Increased knowledge of how Mϕ function is regulated and how polarized Mϕs can be reprogrammed in situ will increase our ability to control Mϕ function in a variety of pathological states, including cancer and chronic inflammatory disease.
TL;DR: Data suggest that alterations in the gene expressions and productions of a number of pro‐ and anti‐inflammatory mediators are present in SCA and importantly, in those patients on HU therapy.
Abstract: Inflammation, cell adhesion to vascular endothelium, and endothelial injury contribute to sickle cell anemia (SCA) vaso-occlusion. Although alterations in inflammatory cytokines and biomarkers have been related, reports have been conflicting, and a conclusive role for these molecules in the disease remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not understood. This study aimed to determine plasma levels and leukocyte gene expressions of inflammatory mediators in healthy controls, steady-state SCA patients, and SCA patients on HU therapy. TNF-alpha, IL-8, and PGE(2) levels were significantly higher in the plasma of SCA individuals when compared with control individuals. HU therapy was associated with a significant reversal of augmented TNF-alpha and, interestingly, increased plasma anti-inflammatory IL-10. IFN-gamma, IL-10, cyclooxygenase 2 (COX-2), and inducible NO synthase (iNOS) gene expressions were unaltered in SCA mononuclear cells (MC); however, gene expressions of TNF-alpha, IL-8, and the protective enzyme heme oxygenase-1 (HO-1) were significantly higher. HU therapy was not associated with significantly altered SCA MC inflammatory gene expression, although COX-2 mRNA expression was decreased. In SCA neutrophils, gene expressions of IL-8, IFN-gamma, iNOS, and HO-1 were significantly higher than those of control subjects. Patients on HU demonstrated lower iNOS and higher IL-10 neutrophil gene expressions. Taken together, data suggest that alterations in the gene expressions and productions of a number of pro- and anti-inflammatory mediators are present in SCA and importantly, in those patients on HU therapy. Knowledge of these pathways may contribute to further the understanding of the pathophysiology of this disease.
TL;DR: Data indicate differential utilization of TLR2 and TLR4 but shared use of MyD88 by fine and coarse air pollution particles.
Abstract: Induction of proinflammatory mediators by alveolar macrophages exposed to ambient air particulate matter has been suggested to be a key factor in the pathogenesis of inflammatory and allergic diseases in the lungs. However, receptors and mechanisms underlying these responses have not been fully elucidated. In this study, we examined whether TLR2, TLR4, and the key adaptor protein, MyD88, mediate the expression of proinflammatory cytokines and chemokines by mouse peritoneal macrophages exposed to fine and coarse PM. TLR2 deficiency blunted macrophage TNF-alpha and IL-6 expression in response to fine (PM2.5), while not affecting cytokine-inducing ability of coarse NIST Standard Reference Material (SRM 1648) particles. In contrast, TLR4(-/-) macrophages showed inhibited cytokine expression upon stimulation with NIST SRM 1648 but exhibited normal responses to PM2.5. Preincubation with polymyxin B markedly suppressed the capacity of NIST SRM 1648 to elicit TNF-alpha and IL-6, indicating endotoxin as a principal inducer of cytokine responses. Overexpression of TLR2 in TLR2/4-deficient human embryonic kidney 293 cells imparted PM2.5 sensitivity, as judged by IL-8 gene expression, whereas NIST SRM 1648, but not PM2.5 elicited IL-8 expression in 293/TLR4/MD-2 transfectants. Engagement of TLR4 by NIST SRM 1648 induced MyD88-independent expression of the chemokine RANTES, while TLR2-reactive NIST IRM PM2.5 failed to up-regulate this response. Consistent with the shared use of MyD88 by TLR2 and TLR4, cytokine responses of MyD88(-/-) macrophages to both types of air PM were significantly reduced. These data indicate differential utilization of TLR2 and TLR4 but shared use of MyD88 by fine and coarse air pollution particles.
TL;DR: RA down‐regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment.
Abstract: IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RARalpha, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RARalpha or LE135 as the antagonist of RARalpha. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression and down-regulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-17) but more regulatory cytokines (IL-10, TGF-beta) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and colon inflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment.
TL;DR: In vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects, suggesting that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis.
Abstract: Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. α-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-α, IL-1β, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production suggested the presence of one or more circulating inhibitors of cytokine synthesis present in blood. Serially diluting blood with tissue-culture medium in the presence of cytokine stimulation with heat-killed Staphylococcus epidermidis (S. epi) resulted in 1.2- to 55-fold increases in cytokine production compared with S. epi stimulation alone. Diluting blood with autologous plasma did not increase the production of IL-8, TNF-α, IL-1β, or IL-1Ra, suggesting that the endogenous, inhibitory activity of blood resided in plasma. In whole blood, diluted and stimulated with S. epi, exogenous AAT inhibited IL-8, IL-6, TNF-α, and IL-1β significantly but did not suppress induction of the anti-inflammatory cytokines IL-1Ra and IL-10. These ex vivo and in vitro observations suggest that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis.
TL;DR: The data suggest that TLR‐dependent, synergistic cytokine gene expression results from enhanced activation and cooperation among NF‐κB, IRF, MAPK, PI‐3K, and STAT signaling pathways.
Abstract: TLRs are innate immune receptors that recognize pathogen-associated structures. Binding of ligands to different TLRs can induce the produc- tion of proinflammatory cytokines in a synergistic manner. We have analyzed the molecular mecha- nisms of synergy in TLR ligand-stimulated human monocyte-derived macrophages and dendritic cells (moDCs). Stimulation of moDCs with the TLR8 ligand together with the TLR3 or TLR4 ligand led to synergistic IL-6, IL-10, IL-12, and TNF- mRNA expression and cytokine production. DNA- binding assays showed that TLR3 and TLR8 stim- ulation induced binding of multiple IFN regulatory factor (IRF) and STAT transcription factors to the IL-12p35 gene promoter IFN-stimulated response element in moDCs and macrophages but with dif- ferent binding profiles and kinetics. We also dem- onstrate that NF-B, MAPKs, and PI-3K pathways have an important role in TLR-induced cytokine gene expression, as pharmacological inhibitors of these signaling pathways inhibited TLR3, TLR4, and TLR8 ligand-induced cytokine mRNA expres- sion and protein production. Especially, synergis- tic IL-12p70 production was abolished completely in NF-B, MAPK p38, and PI-3K inhibitor-treated moDCs. Our data suggest that TLR-dependent, synergistic cytokine gene expression results from enhanced activation and cooperation among NF- B, IRF, MAPK, PI-3K, and STAT signaling pathways. J. Leukoc. Biol. 85: 000-000; 2009.
TL;DR: The HMGB1/RAGE pathway has pathophysiologic and diagnostic significance in experimental colitis and ethyl pyruvate and other strategies to inhibitHMGB1 release and function represent promising interventions in chronic inflammatory diseases.
Abstract: Signals from stressed cells and the enteric microbiota activate macrophages and dendritic cells and mediate intestinal inflammation. HMGB1 serves as an immunogenic stimuli causing release of inflammatory cytokines by myeloid cells. Ethyl pyruvate inhibits secretion of HMGB1 and improves survival in models of endotoxemia and hemorrhagic shock. We reasoned that ethyl pyruvate may be protective in colitis, which involves similar inflammatory pathways. In IL-10−/− mice with established chronic colitis, ethyl pyruvate administration ameliorated colitis and reduced intestinal cytokine production. IL-10−/− mice demonstrated increased intestinal HMGB1 expression and decreased expression of RAGE compared with wild-type mice. Fecal HMGB1 levels were decreased in ethyl pyruvate-treated mice. Furthermore, ethyl pyruvate induced HO-1 expression in intestinal tissue. In TNBS-induced colitis, intrarectal administration of ethyl pyruvate resulted in amelioration of colitis and reduced intestinal cytokine production. In LPS-activated murine macrophages, ethyl pyruvate decreased expression of IL-12 p40 and NO production but did not affect IL-10 levels. Ethyl pyruvate did not inhibit nuclear translocation of NF-κB family members but attenuated NF-κB DNA binding. Additionally, ethyl pyruvate induced HO-1 mRNA and protein expression and HO-1 promoter activation. Moreover, ethyl pyruvate prevented nuclear-to-cytoplasmic translocation of HMGB1. In conclusion, the HMGB1/RAGE pathway has pathophysiologic and diagnostic significance in experimental colitis. Ethyl pyruvate and other strategies to inhibit HMGB1 release and function represent promising interventions in chronic inflammatory diseases.
TL;DR: Using mouse bone marrow‐derived cultured basophils, it is found that IL‐4 and IL‐13 are produced in response to IL‐18 or IL‐33 stimulation, and basophil survival increased in the presence of IL‐ 18 orIL‐33 as a result of increased Akt activation.
Abstract: IL-4 and IL-13 are instrumental in the development and progression of allergy and atopic disease. Basophils represent a key source of these cytokines and produce IL-4 and IL-13 when stimulated with IL-18, a member of the IL-1 family of cytokines. Comparative analyses of the effects of caspase-1-dependent IL-1 family cytokines on basophil IL-4 and IL-13 production have not been performed, and the signaling pathway proteins required for FceRI-independent Th2 cytokine production from basophils remain incompletely defined. Using mouse bone marrow-derived cultured basophils, we found that IL-4 and IL-13 are produced in response to IL-18 or IL-33 stimulation. IL-18- or IL-33-mediated Th2 cytokine production is dependent on MyD88 and p38α signaling proteins. In addition, basophil survival increased in the presence of IL-18 or IL-33 as a result of increased Akt activation. Studies in vivo confirmed the potency of IL-18 and IL-33 in activating cytokine release from mouse basophils.