Role of Innate Immunity in Chronic Kidney Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (16 August 2023) | Viewed by 12227

Special Issue Editor


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Guest Editor
Katz Family Division of Nephrology and Hypertension, Miller School of Medicine, University of Miami, Miami, FL, USA
Interests: kidney; podocytes; lipids; lipid droplet; sphingolipids; innate immunity; diabetic kidney disease; focal segmental glomerulosclerosis
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Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) is a worldwide health problem, with a global estimated prevalence of 16% and costs of USD 7.1 million for renal replacement therapy for patients with end-stage kidney disease. Among the multiple pathogenic mechanisms responsible for CKD, deregulated inflammation, oxidative stress, and immune system activation have deserved significant attention in recent years. More precisely, sterile inflammation triggered by the activation of the innate immune system has been shown to be an important driver of CKD. While our understanding of the innate immune system’s components and ligands, as well as its activation and regulation, has substantially improved in recent years, finding new drug targets and implementations of anti-inflammatory treatments for patients with CKD remains a challenge. This Special Issue will focus on different aspects of innate immunity involvement in CKD development and progression, including molecular, biochemical, and physiological mechanisms. We welcome original basic research and clinical manuscripts, reports on new technologies, methodological reports, and review articles related to the role of innate immunity in CKD.

Dr. Alla Mitrofanova
Guest Editor

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Keywords

  • CKD
  • glomeruli
  • tubules
  • sterile inflammation
  • innate immunity
  • pattern recognition receptors (PRRs)
  • damage-associated molecular patterns (DAMPs)
  • STING
  • Toll-like receptors
  • RIG-I
  • NLRP

Published Papers (5 papers)

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Research

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14 pages, 1893 KiB  
Article
NLRX1 Prevents M2 Macrophage Polarization and Excessive Renal Fibrosis in Chronic Obstructive Nephropathy
by Ye Liu, Lotte Kors, Loes M. Butter, Geurt Stokman, Nike Claessen, Coert J. Zuurbier, Stephen E. Girardin, Jaklien C. Leemans, Sandrine Florquin and Alessandra Tammaro
Cells 2024, 13(1), 23; https://doi.org/10.3390/cells13010023 (registering DOI) - 21 Dec 2023
Viewed by 1883
Abstract
Background: Chronic kidney disease often leads to kidney dysfunction due to renal fibrosis, regardless of the initial cause of kidney damage. Macrophages are crucial players in the progression of renal fibrosis as they stimulate inflammation, activate fibroblasts, and contribute to extracellular matrix deposition, [...] Read more.
Background: Chronic kidney disease often leads to kidney dysfunction due to renal fibrosis, regardless of the initial cause of kidney damage. Macrophages are crucial players in the progression of renal fibrosis as they stimulate inflammation, activate fibroblasts, and contribute to extracellular matrix deposition, influenced by their metabolic state. Nucleotide-binding domain and LRR-containing protein X (NLRX1) is an innate immune receptor independent of inflammasomes and is found in mitochondria, and it plays a role in immune responses and cell metabolism. The specific impact of NLRX1 on macrophages and its involvement in renal fibrosis is not fully understood. Methods: To explore the specific role of NLRX1 in macrophages, bone-marrow-derived macrophages (BMDMs) extracted from wild-type (WT) and NLRX1 knockout (KO) mice were stimulated with pro-inflammatory and pro-fibrotic factors to induce M1 and M2 polarization in vitro. The expression levels of macrophage polarization markers (Nos2, Mgl1, Arg1, and Mrc1), as well as the secretion of transforming growth factor β (TGFβ), were measured using RT-PCR and ELISA. Seahorse-based bioenergetics analysis was used to assess mitochondrial respiration in naïve and polarized BMDMs obtained from WT and NLRX1 KO mice. In vivo, WT and NLRX1 KO mice were subjected to unilateral ureter obstruction (UUO) surgery to induce renal fibrosis. Kidney injury, macrophage phenotypic profile, and fibrosis markers were assessed using RT-PCR. Histological staining (PASD and Sirius red) was used to quantify kidney injury and fibrosis. Results: Compared to the WT group, an increased gene expression of M2 markers—including Mgl1 and Mrc1—and enhanced TGFβ secretion were found in naïve BMDMs extracted from NLRX1 KO mice, indicating functional polarization towards the pro-fibrotic M2 subtype. NLRX1 KO naïve macrophages also showed a significantly enhanced oxygen consumption rate compared to WT cells and increased basal respiration and maximal respiration capacities that equal the level of M2-polarized macrophages. In vivo, we found that NLRX1 KO mice presented enhanced M2 polarization markers together with enhanced tubular injury and fibrosis demonstrated by augmented TGFβ levels, fibronectin, and collagen accumulation. Conclusions: Our findings highlight the unique role of NLRX1 in regulating the metabolism and function of macrophages, ultimately protecting against excessive renal injury and fibrosis in UUO. Full article
(This article belongs to the Special Issue Role of Innate Immunity in Chronic Kidney Diseases)
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13 pages, 1911 KiB  
Article
Expression of Interferon Regulatory Factor 8 (IRF8) and Its Association with Infections in Dialysis Patients
by Justa Friebus-Kardash, Fei Kuang, Tobias Peitz, Thamer A. Hamdan, Ute Eisenberger, Kristina Boss, Andreas Kribben, Karl Sebastian Lang and Michael Jahn
Cells 2023, 12(14), 1892; https://doi.org/10.3390/cells12141892 - 19 Jul 2023
Cited by 1 | Viewed by 982
Abstract
Patients on dialysis have dysfunctions of innate and adaptive immune system responses. The transcriptional factor IRF8 (interferon regulatory factor 8) is primarily expressed in plasmacytoid cells (pDCs) and myeloid dendritic cells (mDCs), playing a crucial role in the maturation of dendritic cells, monocytes, [...] Read more.
Patients on dialysis have dysfunctions of innate and adaptive immune system responses. The transcriptional factor IRF8 (interferon regulatory factor 8) is primarily expressed in plasmacytoid cells (pDCs) and myeloid dendritic cells (mDCs), playing a crucial role in the maturation of dendritic cells, monocytes, and macrophages, and contributing to protection against bacterial infections. The current study analyzed the expression patterns of IRF8 and assessed its association with the risk of infections in 79 dialysis patients compared to 44 healthy controls. Different subsets of leukocytes and the intracellular expression of IRF8 were measured using flow cytometry. Compared to the healthy controls, the dialysis patients showed significantly reduced numbers of pDCs and significantly increased numbers of natural killer cells and classical and intermediate monocytes. The dialysis patients exhibited decreased numbers of IRF8-positive dendritic cells (pDC p < 0.001, mDC1 p < 0.001, mDC2 p = 0.005) and increased numbers of IRF8-positive monocytes (p < 0.001). IRF8 expression in pDC, mDC, and classical monocytes was lower in the dialysis patients than in the controls. Dialysis patients who required hospitalization due to infections within one year of follow-up displayed significantly reduced IRF8 expression levels in pDCs compared to patients without such infections (p = 0.04). Our results suggest that reduced IRF8 expression in pDCs is a potential risk factor predisposing dialysis patients to serious infections. Full article
(This article belongs to the Special Issue Role of Innate Immunity in Chronic Kidney Diseases)
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21 pages, 4003 KiB  
Article
Diagnostic and Prognostic Comparison of Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3 Glomerulopathy
by Marja Kovala, Minna Seppälä, Anne Räisänen-Sokolowski, Seppo Meri, Eero Honkanen and Kati Kaartinen
Cells 2023, 12(5), 712; https://doi.org/10.3390/cells12050712 - 23 Feb 2023
Cited by 6 | Viewed by 2975
Abstract
Membranoproliferative glomerulonephritis (MPGN) is subdivided into immune-complex-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G). Classically, MPGN has a membranoproliferative-type pattern, but other morphologies have also been described depending on the time course and phase of the disease. Our aim was to explore whether the [...] Read more.
Membranoproliferative glomerulonephritis (MPGN) is subdivided into immune-complex-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G). Classically, MPGN has a membranoproliferative-type pattern, but other morphologies have also been described depending on the time course and phase of the disease. Our aim was to explore whether the two diseases are truly different, or merely represent the same disease process. All 60 eligible adult MPGN patients diagnosed between 2006 and 2017 in the Helsinki University Hospital district, Finland, were reviewed retrospectively and asked for a follow-up outpatient visit for extensive laboratory analyses. Thirty-seven (62%) had IC-MPGN and 23 (38%) C3G (including one patient with dense deposit disease, DDD). EGFR was below normal (≤60 mL/min/1.73 m2) in 67% of the entire study population, 58% had nephrotic range proteinuria, and a significant proportion had paraproteins in their serum or urine. A classical MPGN-type pattern was seen in only 34% of the whole study population and histological features were similarly distributed. Treatments at baseline or during follow-up did not differ between the groups, nor were there significant differences observed in complement activity or component levels at the follow-up visit. The risk of end-stage kidney disease and survival probability were similar in the groups. IC-MPGN and C3G have surprisingly similar characteristics, kidney and overall survival, which suggests that the current subdivision of MPGN does not add substantial clinical value to the assessment of renal prognosis. The high proportion of paraproteins in patient sera or in urine suggests their involvement in disease development. Full article
(This article belongs to the Special Issue Role of Innate Immunity in Chronic Kidney Diseases)
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Review

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14 pages, 944 KiB  
Review
Innate Immunity and CKD: Is There a Significant Association?
by Moran Plonsky-Toder, Daniella Magen and Shirley Pollack
Cells 2023, 12(23), 2714; https://doi.org/10.3390/cells12232714 - 27 Nov 2023
Viewed by 1338
Abstract
Chronic kidney disease (CKD) constitutes a worldwide epidemic, affecting approximately 10% of the global population, and imposes significant medical, psychological, and financial burdens on society. Individuals with CKD often face elevated morbidity and mortality rates, mainly due to premature cardiovascular events. Chronic inflammation [...] Read more.
Chronic kidney disease (CKD) constitutes a worldwide epidemic, affecting approximately 10% of the global population, and imposes significant medical, psychological, and financial burdens on society. Individuals with CKD often face elevated morbidity and mortality rates, mainly due to premature cardiovascular events. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications, including atherosclerosis, cardiovascular disease (CVD), protein–energy wasting, and the aging process. Over the past two decades, a substantial body of evidence has emerged, identifying chronic inflammation as a central element of the uremic phenotype. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications in dialysis patients, including atherosclerosis, CVD, protein–energy wasting, and the aging process. Remarkably, chronic inflammation also impacts patients with CKD who have not yet required renal replacement therapy. While extensive research has been conducted on the involvement of both the adaptive and innate immune systems in the pathogenesis of CKD-related complications, this wealth of data has not yet yielded well-established, effective treatments to counteract this ongoing pathological process. In the following review, we will examine the established components of the innate immune system known to be activated in CKD and provide an overview of the current therapeutic approaches designed to mitigate CKD-related chronic inflammation. Full article
(This article belongs to the Special Issue Role of Innate Immunity in Chronic Kidney Diseases)
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20 pages, 713 KiB  
Review
The Role of Inflammation in CKD
by Saurav Prashant Kadatane, Matthew Satariano, Michael Massey, Kai Mongan and Rupesh Raina
Cells 2023, 12(12), 1581; https://doi.org/10.3390/cells12121581 - 7 Jun 2023
Cited by 32 | Viewed by 4275
Abstract
Chronic kidney disease (CKD) affects many adults worldwide. Persistent low-grade inflammation is a substantial factor in its development and progression and has correlated with increased mortality and cardiovascular problems. This low-grade inflammation is a product of dysregulation of the normal balance between pro- [...] Read more.
Chronic kidney disease (CKD) affects many adults worldwide. Persistent low-grade inflammation is a substantial factor in its development and progression and has correlated with increased mortality and cardiovascular problems. This low-grade inflammation is a product of dysregulation of the normal balance between pro- and anti-inflammatory markers. Various factors such as increased innate immune system activation, reactive oxygen species production, periodontal disease, dysregulation of anti-inflammatory systems and intestinal dysbiosis result in the dysregulation of this balance. Furthermore, this low-grade inflammation has down-effects such as hypertension, renal fibrosis and acceleration of renal function decline. Moreover, low-grade inflammation over time has been linked to malignancy in CKD. As CKD progresses, many patients require dialysis, which has a negative bidirectional relationship with persistent inflammation. Treatment options for inflammation in CKD are vast, including cytokine inhibitors, statins and diets. However, more research is needed to create a standardized management plan. In this review, we will examine the normal physiology of the kidney and its relationship with the immune system. We will then delve into the pathology behind persistent inflammation, the various causes of inflammation, the downstream effects of inflammation, dialysis and potential treatments for inflammation in CKD. Full article
(This article belongs to the Special Issue Role of Innate Immunity in Chronic Kidney Diseases)
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