Researchers at Zhejiang University School of Medicine, China, studied how the innate immune system of kidney macrophages works to prevent stones kidneys. The investigators detailed their findings on the mechanistic actions and strategic positioning of macrophages to surveil epithelial cells and intratubular environments.
The results of the study were published in Immunity.
Kidney macrophages: here's why they are so important
As urine passes through the tubular system of the kidneys, various microscopic sediment particles, including mineral crystals, are generated from the concentrated urine. Pathological conditions can lead to the presence of inflammatory proteins and cells. These particles can lodge in the tubules, blocking the flow of urine and causing kidney dysfunction.
The researchers observed kidney macrophages adjacent to the tubules in real time, using high-resolution microscopy, live recordings, and two-photon microscopy techniques. They were able to record renal macrophages extending transepithelial protrusions and interacting with intratubular particles, as well as their migration to promote excretion of urine particles.
These techniques captured the association of macrophages with particles in urine and demonstrated the role of renal macrophages in particle removal. Renal macrophages located near the medullary tubules exhibit specific behaviors, extending transepithelial protrusions and constantly sampling urine contents.
It was then seen that the macrophages migrated and surrounded the intratubular particles, favoring their removal from the tubular system. Mice were injected with inert fluorescent latex beads into the kidney and within 12 hours free beads were almost absent from the lumen of the collecting ducts.
To confirm the role of macrophages, the latex bead experiment was repeated with mice lacking renal macrophages. Macrophage-depleted mice showed increased retention of fluorescent beads even after 36 hours, despite longer exposure to natural urine washing.
This result suggests that normal urine flushing alone could not efficiently remove large particles in the renal tubule system without preliminary assistance in macrophage clearance.
The findings suggest potential therapeutic implications for kidney stones (nephrolithiasis or kidney stones) and for the development of kidney-specific drug delivery methods based on these distinctive features of renal macrophages.
Acute kidney injury (AKI) is a condition in which the kidneys are unable to effectively filter waste from the blood, leading to various health complications. Numerous studies have shown that acute kidney injury (AKI) subsequently leads to long-term kidney damage and progresses to chronic kidney disease (CKD), a more severe form of kidney failure. The transition from AKI to CKD depends on various factors, such as sepsis, the type of surgery and the presence of cardiovascular disease.
At present, the exact mechanisms underlying this multifactorial transition are unclear. Unraveling these mechanisms may contribute to the development of therapeutic strategies to prevent the AKI-CKD transition. It is currently known that renal macrophages, which are a type of immune cell, play a key role in the transition from AKI to CKD.
To further explore the role of macrophages, a team of researchers led by Dr. Xiaoming Meng from Anhui Medical University in China wrote a review article highlighting the impact of different macrophage subtypes on the transition from AKI to CKD. This article, published in the Chinese Medical Journal, also explored the potential of macrophage-targeted therapy in preventing AKI-CKD transition.
The source from which a macrophage is derived influences its phenotype and function. Indeed, renal macrophages can evolve into multiple phenotypes, each of which takes on a different role in the regulation of renal failure and repair. For example, resident macrophages, which are specific to kidney tissue, are involved in anti-inflammatory processes during kidney repair, while circulating macrophages, which are derived from blood monocytes, play a proinflammatory role when they migrate to the site of injury.
Generally, macrophages are classified into two types: M1 and M2. Some studies have suggested that M1 macrophages, which are proinflammatory, play a role in some early processes associated with the development of AKI. On the other hand, M2 macrophages have been found to reduce AKI-associated inflammation and fibrosis.
How do proinflammatory macrophages contribute to chronic kidney disease? Dr. Meng states that “kidney damage leading to chronic kidney disease is enhanced by proinflammatory macrophages. These macrophages accelerate renal inflammation through the release of several proinflammatory cytokines and chemokines or by triggering abnormal wound healing processes, which ultimately leads to renal fibrosis.” .”
The unique nature of renal macrophages allows them to change their phenotype from M1 to M2 in response to renal damage, a process known as polarization. Macrophages can also alter the renal microenvironment through interactions with endothelial cells, immune cells, fibroblasts, and tubular epithelial cells (TECs). For example, macrophages infiltrating the kidney in response to injury promote TEC damage and death, which ultimately blocks the TEC-driven AKI-CKD transition.
In sepsis-induced AKI, Csf2, which is a cytokine secreted by damaged TECs, promotes the transition of M1 macrophages to M2 macrophages. Interestingly, some M2 macrophages expressing CD206 and/or CD163 receptors contribute to subclinical inflammation, tubular damage, and progression of renal fibrosis, in stark contrast to their usual anti-inflammatory behavior.
Furthermore, in cases of extreme inflammation, M2 macrophages adopt a “pro-fibrotic phenotype” in which they activate myofibroblasts, which are cells involved in wound contraction and healing.
“Unexpectedly, we discovered that renal macrophages can transdifferentiate directly into myofibroblasts, through a process known as macrophage-myofibroblast transition (MMT). Th
ese newly formed myofibroblasts increase renal fibrosis, which ultimately leads to renal failure,” said Dr. Meng. At present, the exact role of MMT in the AKI-CKD transition is unclear.
The article also discusses three signaling pathways that contribute to the transition from AKI to CKD, which include the Notch signaling pathway, the TGF-β/Smad signaling pathway, and the Wnt/β-catenin signaling pathway.
“Attacking pathways that regulate macrophage and MMT activation or modification of macrophage phenotypes may be a promising therapeutic approach for kidney disease, blocking the transition from AKI to CKD,” says Dr. Meng, while discussing how prevent the transition from AKI to CKD.
Therapeutic strategies that interfere with the activation and pathogenic role of macrophages in this transition have been extensively studied. The article highlights the role of molecules known as clodronate liposomes, which can deplete macrophages and reduce the extent of renal fibrosis. Altering the activation of renal macrophages and the blocking factors with which they interact may also prevent renal fibrosis and subsequent failure.
Additionally, treatment with a compound known as quercetin has been shown to block renal macrophage infiltration and M2 polarization. Additionally, a receptor known as colony-stimulating factor (CSF)-1 influences the proliferation, differentiation, and survival of macrophages.
Blocking the gene coding for this receptor can lead to an inhibition of the proliferation of renal macrophages. Additionally, a molecule known as vorapaxar has been reported to suppress macrophages by blocking pathways involved in the transition from AKI to CKD.
Kidney macrophages are immune cells that engulf and digest pathogens, tumor cells, or cellular debris. The kidneys, like other tissues in the body, contain kidney-resident macrophages, or KRMs, from the time of birth. These KRMs protect the kidney from infection or injury and help maintain tissue health by phagocytosis of debris or dying kidney cells.
In other organs, the location of macrophages influences their functions. Now James George, Ph.D., and colleagues at the University of Alabama at Birmingham report for the first time that the mouse kidney contains seven distinct KRM populations located in spatially discrete microenvironments and that each subpopulation has a unique transcriptomic signature – a measure of which genes are active, which suggests distinct functions.
“The layering of KRMs in specific areas within the kidney was previously unknown,” George said. “The spatial location of renal macrophages affects their function in other tissues, such as the lung, spleen and liver, and shapes their response to an immunological challenge.
Although many disease states have known connections to KRMs and targeting populations holds great therapeutic promise, the successful design and implementation of such strategies is limited by our current understanding of KRM regulation and injury response as a function of time”.
The UAB study , published in the journal JCI Insight, is an application of spatial transcriptomics, which Nature Methods crowned the 2020 Method of the Year.
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