Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A ...variant that alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in FcγRIIA affinity would affect inflammation in an IgA-dominated organ. We found a profound induction of anti-commensal IgG and a concomitant increase in activating FcγR signaling in the colonic mucosa of UC patients. Commensal-IgG immune complexes engaged gut-resident FcγR-expressing macrophages, inducing NLRP3- and reactive-oxygen-species-dependent production of interleukin-1β (IL-1β) and neutrophil-recruiting chemokines. These responses were modulated by the FCGR2A genotype. In vivo manipulation of macrophage FcγR signal strength in a mouse model of UC determined the magnitude of intestinal inflammation and IL-1β-dependent type 17 immunity. The identification of an important contribution of IgG-FcγR-dependent inflammation to UC has therapeutic implications.
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•Intestinal inflammation in UC is associated with increased anti-commensal IgG•Commensal-IgG cross-link FcγR on colonic MNPs, inducing IL-1β production•MNP FcγR A:I ratio determines magnitude of type 17 immunity and local inflammation•Identifies cellular mechanisms by which FcγRIIA H/R131 confers UC susceptibility
Castro-Dopico et al. find a profound induction of anti-commensal IgG in the colonic mucosa of UC patients and outline a pathway whereby FcγR receptor activation by IgG leads to IL-1β production, type 17 immunity, and the exacerbation of inflammation. Their findings reveal an important contribution of IgG-mediated inflammation in an IgA-dominated organ.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed ...tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony ...stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.
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•ILCs are a major source of GM-CSF, a critical regulator of gut inflammatory macrophages•GM-CSF promotes ILC-macrophage crosstalk and augments type 17 and barrier immunity•GM-CSF-induced macrophages are protective during infection but drive inflammatory colitis•GM-CSF suppresses wound-healing macrophage response associated with intestinal fibrosis
Castro-Dopico et al. identify GM-CSF as a major upstream regulator of intestinal inflammatory macrophages, with ILC-derived GM-CSF polarizing macrophages toward a glycolytic, anti-microbial phenotype while suppressing wound-healing, pro-fibrotic activity. GM-CSF initiates further ILC-macrophage crosstalk, amplifying ILC3 activation and type 17 immunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Tissue-resident macrophages and dendritic cells respond to immunological challenges within an organ. The kidney is a unique environment for these cells, with extreme but variable ...hypersalinity in the medulla, generated by urine concentration mechanisms. Lower urinary tract infections are one of the commonest human bacterial infections, yet renal involvement is rare. Mechanical forces, such as anterograde urine flow can be protective. We aimed to determine whether additional tissue-specific mechanisms protect the kidney. Methods We characterised macrophages and dendritic cells (mononuclear phagocytes MNP) in human kidneys, and evaluated their role in defence against uropathogenic Escherichia coli (UPEC). We used murine models and mouse and human cells in culture to investigate the factors controlling MNP positioning in the medulla and, together with human epidemiological datasets, to determine the importance of the renal sodium gradient in defence against urinary tract infection. Findings We found that physiological hypersalinity provided a cue to renal tubular epithelial cells, stimulating TonEBP-dependent production of chemokines (CCL2 and CX3CL1) that orchestrate the recruitment of CD14+ macrophages to the medulla. These CD14+ macrophages were adept at phagocytosis of UPEC, and their bactericidal and neutrophil chemotactic function was further enhanced by hypersalinity. In murine models, we confirmed that these macrophages were derived from monocytes and that their medullary localisation was CCR2-dependent. Finally, we demonstrated the relevance of these observations in vivo, showing that disruption of the renal sodium gradient in patients and mice led to aberrant chemokine expression and macrophage localisation, and susceptibility to pyelonephritis. Interpretation We have shown a novel mechanism whereby changes in the tissue environment generated by the homoeostatic function of an organ stimulate epithelial–macrophage crosstalk to optimise defence against infection. Funding Medical Research Council, Kidney Research UK.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
IgG antibodies form immune complexes (IC) that propagate inflammation and tissue damage in autoimmune diseases such as systemic lupus erythematosus. IgG IC engage Fcγ receptors (FcγR) on mononuclear ...phagocytes (MNP), leading to widespread changes in gene expression that mediate antibody effector function. Bromodomain and extra-terminal domain (BET) proteins are involved in governing gene transcription. We investigated the capacity of BET protein inhibitors (iBET) to alter IgG FcγR-mediated MNP activation. We found that iBET dampened IgG IC-induced pro-inflammatory gene expression and decreased activating FcγR expression on MNPs, reducing their ability to respond to IgG IC. Despite FcγR downregulation, iBET-treated macrophages demonstrated increased phagocytosis of protein antigen, IgG IC, and apoptotic cells. iBET also altered cell morphology, generating more amoeboid MNPs with reduced adhesion. iBET treatment impaired chemotaxis towards a CCL19 gradient in IC-stimulated dendritic cells (DC)
, and inhibited IC-induced DC migration to draining lymph nodes
, in a DC-intrinsic manner. Altogether, our data show that iBET modulates FcγR-mediated MNP activation and migration, revealing the therapeutic potential of BET protein inhibition in antibody-mediated diseases.
Lower urinary tract infections are among the most common human bacterial infections, but extension to the kidneys is rare. This has been attributed to mechanical forces, such as urine flow, that ...prevent the ascent of bladder microbes. Here, we show that the regional hypersalinity, required for the kidney’s urine-concentrating function, instructs epithelial cells to produce chemokines that localize monocyte-derived mononuclear phagocytes (MNPs) to the medulla. This hypersaline environment also increases the intrinsic bactericidal and neutrophil chemotactic activities of MNPs to generate a zone of defense. Because MNP positioning and function are dynamically regulated by the renal salt gradient, we find that patients with urinary concentrating defects are susceptible to kidney infection. Our work reveals a critical accessory role for the homeostatic function of a vital organ in optimizing tissue defense.
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•Medullary sodium stimulates NFAT5-dependent epithelial chemokine production•Monocytes are recruited to the medulla via CCR2-CCL2-dependent chemotaxis•Hypersalinity enhances MNP bactericidal activity and cytokine production•Responsive medullary defense zone calibrates defense against ascending infection
Sodium gradient guides the migration of innate immune cells in the kidney during infections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The metabolic state of an immune cell directly influences its ability to function and differentiate, ultimately affecting immunity, inflammation and tolerance. Different immune cell subsets have ...differing metabolic requirements. Macrophages, as the frontline, tissue-resident cells of the innate immune system, undergo profound metabolic reprogramming in response to environmental stimuli. To date, there has been little consideration how macrophage metabolism might be affected by humoral immunity. IgG antibodies are the soluble effector molecules of the adaptive humoral immune system. Fcγ receptors (FcγRs) mediate the cellular functions of IgG antibodies and are expressed on most immune cells including macrophages. FcγR cross-linking induced by IgG immune complexes (ICs) is important for defence against some infections but can also play a pathogenic role in autoimmunity. Here, I studied the metabolic reprogramming induced in macrophages by IgG IC ligation of FcγRs. I first investigated how FcγRs cross-linking might impact glucose metabolism. We show that macrophages undergo a switch to glycolysis in response to IgG IC stimulation. FcγR-associated glycolysis was dependent on the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor (HIF)1α. Moreover, this glycolytic switch was required to generate a number of pro-inflammatory mediators and cytokines. Inhibition of glycolysis, or genetic depletion of HIF1α in macrophages resulted in the attenuation of IL1β and other inflammatory mediators produced in response to IgG IC in vitro. To determine the relevance of these observations to responses to IgG IC in vivo and, in particular, to IC-associated tissue inflammation in autoimmune diseases such as system lupus erythematosus (SLE), I developed three models to interrogate tissue macrophages. Following administration of IC to peritoneal macrophages, I observed IL1β-associated neutrophil recruitment that was abrogated by inhibiting glycolysis, or in the presence of HIF-1a deficiency. Similarly, following administration of intravenous IC, or nephrotoxic serum, kidney macrophage activation was abrogated by glycolysis inhibition or by myeloid HIF-1a deficiency. Together my data reveal the cellular molecular mechanisms required for FcγR-mediated metabolic reprogramming in macrophages and define a novel therapeutic strategy in autoantibody-induced inflammation. In the final part of the thesis I identified additional metabolic pathways that were altered by FcγR ligation, including cholesterol biosynthesis and fatty acid biosynthesis. This has important implications for protective immune responses and autoimmune susceptibility, since a number of intermediates in these pathways can directly regulate and contribute to immune responses. In summary, I have demonstrated the metabolic alterations triggered by FcγR ligation, reveal the cellular molecular mechanisms required for FcγR-mediated cellular respiration reprogramming in macrophages and define a potential therapeutic target in autoimmunity.
The aim of the present work is to prepare polymeric materials and to be used as drag reducer. In this paper, a new type of drag reducer was synthesized with polymeric materials. Technically, N, ...N-dimethyl-N-hexadecyl allylammonium bromide (DHAB) was synthesized with 3-bromopropene and N, N-dimethylcetyl tertiary amine, and then cationic hydrophobically associating polyacrylamide P(AM-DHAB), the desired drag reducer, was synthesized. The chemical structures of the products were confirmed by IR and NMR. The molecular weight of the drag reducer was found to be 2.66 × 10
6
g/mol as measured by laser light scattering method. In fresh water, when the concentration of drag reducer is 0.03%, the highest drag reduction rate is reached up to 73.05%. However, when the concentration of drag reducer is further increased, the viscosity is increased and drag reduction rate is decreased; indicating high viscosity has a significant negative effect on drag reduction rate. While in brine, with a viscosity obviously lower than that in fresh water, the drag reduction rate was slightly lower than 70% when the concentration of drag reducer was 0.03%; increasing the concentration of P(AM-DHAB) did not lead to a significant increase in viscosity, instead, it caused the drag reduction rate to be higher than 70%. Therefore, low viscosity facilitates drag reduction performance. Potassium persulfate makes the viscosity of slick water decrease sharply, which helps promote the polymer degradation and thus prevent polymer damage to the reservoir. Scanning electron microscope (SEM) showed that the drag reducer featured an obvious network structure in fresh water before gel breaking, and that there was almost no network structure but a small number of crystallites after gel breaks. In contrast, in brine, no matter before and after gel breaking, only salt crystals were cleanly seen under electron microscope due to high concentration of salt.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Few studies have focused on the potential impacts of topography on regional crop simulation, which might constrain the development of crop models and lead to inaccurate estimations for food security. ...In this study, we used remote sensing data to calibrate a regional crop model (MCWLA-Rice) for yield simulation in a double-rice crop rotation system in counties of Hunan province dominated by three landforms (plain, hill, and mountain). The calibration scheme with coarse remote sensing data (Global LAnd Surface Satellite, GLASS) greatly improved model accuracy for the double-rice system and is a promising method for yield estimation in large areas. The average improvement in relative root mean square error (RRMSE) was at most 48.00% for early rice and 41.25% for late rice. The average improvement in coefficient of determination (R2) value was at most 0.54 for early rice and 0.19 for late rice. Estimation of yield in counties dominated by different landform types indicated that: (1) MCWLA-Rice tended to be unstable in areas of complex topography and resulted in unbalanced proportions of overestimations and underestimations. (2) Differences in yield simulation between early rice and late rice varied among counties; yield estimates were highest in predominantly hilly counties, followed by counties dominated by plains, and lowest in predominantly mountainous counties. The results indicated that the topography might harm the accuracy of crop model simulations. Integration of topographic factors into crop models may enable yield estimation with enhanced accuracy to promote social development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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