Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Both conditions are rising in incidence as well as prevalence, creating poor outcomes for ...patients and high healthcare costs. Recent data suggests CKD to be an independent risk factor for CVD. Accumulation of uremic toxins, chronic inflammation, and oxidative stress have been identified to act as CKD-specific alterations that increase cardiovascular risk. The association between CKD and cardiovascular mortality is markedly influenced through vascular alterations, in particular atherosclerosis and vascular calcification (VC). While numerous risk factors promote atherosclerosis by inducing endothelial dysfunction and its progress to vascular structural damage, CKD affects the medial layer of blood vessels primarily through VC. Ongoing research has identified VC to be a multifactorial, cell-mediated process in which numerous abnormalities like mineral dysregulation and especially hyperphosphatemia induce a phenotype switch of vascular smooth muscle cells to osteoblast-like cells. A combination of pro-calcifying stimuli and an impairment of inhibiting mechanisms like fetuin A and vitamin K-dependent proteins like matrix Gla protein and Gla-rich protein leads to mineralization of the extracellular matrix. In view of recent studies, intercellular communication pathways via extracellular vesicles and microRNAs represent key mechanisms in VC and thereby a promising field to a deeper understanding of the involved pathomechanisms. In this review, we provide an overview about pathophysiological mechanisms connecting CKD and CVD. Special emphasis is laid on vascular alterations and more recently discovered molecular pathways which present possible new therapeutic targets.
Attraction, retention, and differentiation of leukocytes to and within the kidney are governed by chemokines. The chemokine CX3CL1 (fractalkine) and its receptor CX3CR1 are exemplary in this regard ...as they are highly expressed and further upregulated in a range of kidney diseases. CX3CL1 is chiefly produced by renal endothelium and tubular epithelium, where it promotes leukocyte attraction. Recent data suggest that in addition to established soluble mediators, cellular interactions may enhance CX3CL1 expression. The receptor CX3CR1 is essential in myeloid phagocyte homing to the kidney at homeostasis, after acute cell depletion and in inflammation. CX3CR1 and its ligand are highly regulated in human kidney diseases such as IgA nephritis, systemic lupus erythematosus, and inflammatory conditions such as transplant rejection. A mechanistic role of CX3CR1 has been established in experimental models of nephrotoxic nephritis and renal candidiasis. It is debated in fibrosis. Recent publications demonstrate a role for CX3CR1
+
myeloid cells in radio-contrast-agent and sepsis-induced kidney damage. Systemically, circulating CX3CR1
+
monocytes reversibly increase in individuals with renal impairment and correlate with their cardiovascular risk. In this review, we discuss role and regulatory mechanisms of the CX3CL1-CX3CR1 axis in both localized and systemic effects of renal inflammation.
Dendritic cells (DCs) are chief inducers of adaptive immunity and regulate local inflammatory responses across the body. Together with macrophages, the other main type of mononuclear phagocyte, DCs ...constitute the most abundant component of the intrarenal immune system. This network of functionally specialized immune cells constantly surveys its microenvironment for signs of injury or infection, which trigger the initiation of an immune response. In the healthy kidney, DCs coordinate effective immune responses, for example, by recruiting neutrophils for bacterial clearance in pyelonephritis. The pro-inflammatory actions of DCs can, however, also contribute to tissue damage in various types of acute kidney injury and chronic glomerulonephritis, as DCs recruit and activate effector T cells, which release toxic mediators and maintain tubulointerstitial immune infiltrates. These actions are counterbalanced by DC subsets that promote the activation and maintenance of regulatory T cells to support resolution of the immune response and allow kidney repair. Several studies have investigated the multiple roles for DCs in kidney homeostasis and disease, but it has become clear that current tools and subset markers are not sufficient to accurately distinguish DCs from macrophages. Multidimensional transcriptomic analysis studies promise to improve mononuclear phagocyte classification and provide a clearer view of DC ontogeny and subsets.
Antiviral or antitumor immunity requires activation of cytotoxic CD8+ T cells by dendritic cells, which present viral or tumor antigens on major histocompatibility complex (MHC) class I molecules. ...The intracellular mechanisms facilitating MHC class I-restricted presentation of extracellular antigens ('cross-presentation') are unclear. Here we demonstrate that cross-presentation of soluble antigen occurred in an early endosomal compartment distinct from the endoplasmic reticulum where endogenous antigen is loaded onto MHC class I. Efficient cross-presentation required endotoxin-induced, Toll-like receptor 4- and signaling molecule MyD88-dependent relocation of the transporter associated with antigen processing, essential for loading of MHC class I, to early endosomes. Transport of cross-presented antigen from endosomes to the cell surface was inhibited by primaquine, which blocks endosomal trafficking. Thus, cross-presentation is spatially and mechanistically separated from endogenous MHC class I-restricted antigen presentation and is biased toward antigens containing microbial molecular patterns.
The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against ...particle‐bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune‐mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low‐dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy‐based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte‐derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle‐associated antigens in homeostasis. KC‐associated antigen presentation induces CD4 T‐cell arrest, expansion of naturally occurring Foxp3+CD25+ interleukin‐10‐producing antigen‐specific regulatory T cells (Tregs) and tolerogenic immunity. Particle‐associated tolerance induction in the liver protected mice from kidney inflammation in T‐cell‐mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune‐mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen‐specific CD4 T cells. In injured liver, infiltrating monocyte‐derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype. Conclusions: Hepatic induction of tissue‐protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases. (Hepatology 2015;62:279‐291)
Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling ...mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.
The total number of glomeruli is a fundamental parameter of kidney function but very difficult to determine using standard methodology. Here, we counted all individual glomeruli in murine kidneys and ...sized the capillary tufts by combining in vivo fluorescence labeling of endothelial cells, a novel tissue-clearing technique, lightsheet microscopy, and automated registration by image analysis. Total hands-on time per organ was <1 hour, and automated counting/sizing was finished in <3 hours. We also investigated the novel use of ethyl-3-phenylprop-2-enoate (ethyl cinnamate) as a nontoxic solvent-based clearing reagent that can be handled without specific safety measures. Ethyl cinnamate rapidly cleared all tested organs, including calcified bone, but the fluorescence of proteins and immunohistochemical labels was maintained over weeks. Using ethyl cinnamate-cleared kidneys, we also quantified the average creatinine clearance rate per glomerulus. This parameter decreased in the first week of experimental nephrotoxic nephritis, whereas reduction in glomerular numbers occurred much later. Our approach delivers fundamental parameters of renal function, and because of its ease of use and speed, it is suitable for high-throughput analysis and could greatly facilitate studies of the effect of kidney diseases on whole-organ physiology.
The Janus kinase (JAK)–inhibitor ruxolitinib decreases constitutional symptoms and spleen size of myelofibrosis (MF) patients by mechanisms distinct from its anticlonal activity. Here we investigated ...whether ruxolitinib affects dendritic cell (DC) biology. The in vitro development of monocyte-derived DCs was almost completely blocked when the compound was added throughout the differentiation period. Furthermore, when applied solely during the final lipopolysaccharide-induced maturation step, ruxolitinib reduced DC activation as demonstrated by decreased interleukin-12 production and attenuated expression of activation markers. Ruxolitinib also impaired both in vitro and in vivo DC migration. Dysfunction of ruxolitinib-exposed DCs was further underlined by their impaired induction of allogeneic and antigen-specific T-cell responses. Ruxolitinib-treated mice immunized with ovalbumin (OVA)/CpG induced markedly reduced in vivo activation and proliferation of OVA-specific CD8+ T cells compared with vehicle-treated controls. Finally, using an adenoviral infection model, we show that ruxolitinib-exposed mice exhibit delayed adenoviral clearance. Our results demonstrate that ruxolitinib significantly affects DC differentiation and function leading to impaired T-cell activation. DC dysfunction may result in increased infection rates in ruxolitinib-treated patients. However, our findings may also explain the outstanding anti-inflammatory and immunomodulating activity of JAK inhibitors currently used in the treatment of MF and autoimmune diseases.
•The JAK-inhibitor ruxolitinib affects dendritic cell differentiation, phenotype, and function leading to impaired T-cell activation.
Salt, inflammation, IL‐17 and hypertension Wenzel, Ulrich O; Bode, Marlies; Kurts, Christian ...
British journal of pharmacology,
June 2019, Volume:
176, Issue:
12
Journal Article
Peer reviewed
Open access
Traditionally, arterial hypertension and subsequent end‐organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the ...deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Over the past few years, important findings have revolutionized hypertension research. Firstly, in 2007, a seminal paper showed that adaptive immunity is involved in the pathogenesis of hypertension. Secondly, salt storage in the skin and its consequences for cardiovascular physiology were discovered. Thirdly, after the discovery that salt promotes the differentiation of CD4+ T cells into TH17 cells, it was demonstrated that salt directly changes several cells of the innate and adaptive immune system and aggravates autoimmune disease but may improve antimicrobial defence. Herein, we will review pathways of activation of immune cells by salt in hypertension as the framework for understanding the multiple roles of salt and immunity in arterial hypertension and autoimmune disease.
Linked Articles
This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc
Intrarenal crystal formation activates the Nlrp3 inflammasome in myeloid cells and triggers a profound inflammatory response. Here, we studied whether a specific inhibitor of the Nlrp3 inflammasome, ...CP-456,773, can prevent kidney fibrosis in a murine model of crystal nephropathy induced by diets rich in oxalate or adenine. Inflammasome activation in renal dendritic cells and the resulting interleukin (IL)-1β and IL-18 production were markedly reduced by CP-456,773 treatment both ex vivo and in vivo. We directly visualized intrarenal inflammasome activation and its inhibition by CP-456,773 in vivo by adoptive transfer of bone marrow cells transduced with interleukin-1β-Gaussia luciferase, a proteolytic luciferase-based reporter for inflammasome activation, into irradiated mice. CP-456,773 treatment strongly attenuated kidney fibrosis when given early in the genesis of crystal nephropathy, but was unable to reverse established crystal-induced fibrosis. The urinary IL-18 concentration appeared to be a useful noninvasive biomarker for renal inflammasome activation. Finally, NLRP3 inhibition did not compromise adaptive immune responses as previously reported for the global inhibition of IL-1 signaling. Thus, early NLRP3 inhibition by CP-456,773 may be an effective treatment for crystal nephropathy. Use of iGLuc transfected cells introduces a novel imaging technique for inflammasome activation in mice.
PDF
