Acute kidney injury (AKI) is associated with high morbidity and mortality rates, primarily due to the lack of effective therapeutic options for kidney repair. To restore the biological function of injured kidney, there is a need to protect renal tubular epithelial cells (RTECs) and regulate M1 macrophages, responsible for progress of AKI. Herein, based on metabolic glycoengineering-mediated click chemistry, we prepare the engineered extracellular vesicles (pSEVs), derived from PEGylated hyaluronic acid (HA)-modified mesenchymal stem cells. Owing to their cell-protective and anti-inflammatory properties, pSEVs effectively prevent the apoptosis of RTECs and inhibit the polarization of macrophages into an inflammatory phenotype in vitro. When systemically administered into the cisplatin-induced AKI animal model, pSEVs selectively accumulate in injured kidneys via HA-mediated binding to CD44 and toll-like receptor4 which are over-expressed on RTECs and M1 macrophages, respectively. This targeted delivery efficiently alleviates AKI-related symptoms, as evidenced by delayed kidney weight reduction, and decreased levels of creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin. Overall, pSEVs show potent anti-inflammatory effects and specific targeting to injured kidneys, presenting a considerable potential as the therapeutics for AKI.

Macrophages are key cells in the immune response, and their abnormal infiltration into the kidney is a common pathological feature in kidney diseases. Exosomes, acting as carriers for transporting essential proteins and genetic materials, can be derived from various cell types and are involved in a wide range of physiological and pathological processes in the kidney. As primary inflammatory immune cells, macrophages have garnered significant attention from scholars regarding the effects of their secreted exosomes on renal intrinsic cells in kidney diseases, as well as the interactive effects of exosomes derived from other cells on macrophages. This review delves into the detailed characteristics of macrophage-derived exosomes in kidney diseases, the mechanisms by which they promote damage to specific cells, and the signaling pathways involved. Additionally, it examines the reverse direction, elucidating the circulatory mechanisms of substances carried by exosomes from renal intrinsic cells that induce phenotypic transformation and inflammatory responses in macrophages, ultimately leading to further damage of renal intrinsic cells. The pathological role of exosome-macrophage interconnections in various renal diseases has received increasing attention, and understanding this mechanism can help unravel the microscopic immunoregulatory processes underlying kidney diseases. Moreover, the identification of therapeutic targets related to macrophage-related exosomes offers new strategies for the treatment of these conditions.

Immunotherapy has paramount importance in treating chronic immune diseases, and vaccine development. Hyaluronic acid (HA) has been shown to elicit molecular weight-related distinct immune responses. Nonetheless, the particle size-dependent immunomodulatory effects of hyaluronic acid nanoparticles (HA-NPs) remain blurred. Thus, the present study aimed at investigating the effect of polymer configuration and particle size of HA-NPs assembled from HA36K-ODA and HA360k-ODA analogs in modulating macrophage-related immune activities. In the in vitro experiments, HA-NPs of HA36k-ODA analogs garnered significantly enhanced nitrite production with low interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) secretion in macrophages. Furthermore, smaller (< 200 nm) HA36k-ODA NPs activated CD11b+ cells whereas a ∼ 130 nm HA36k-ODA15 NPs preferentially induced CD11c+ cells in vivo, indicating the influence of particle size on the antigen-presenting cells (APCs) recruitment. Interestingly, self-assembled HA36k-ODA15 NPs without ovalbumin (OVA) activated immature dendritic cells (DCs) and augmented their migration toward the lymph nodes (LNs). Notably, HA36k-ODA15-activated macrophages behaved like M1 phenotype macrophages. Overall, our findings garnered valuable insights about the design and application of HA-NPs for modulating the immune responses in nanoscale materials-based immunotherapy.

Chronic kidney disease (CKD) is characterised by inflammation, which can lead to tubular atrophy and fibrosis. The molecular mechanisms are not well understood. In this study, we investigated the functional role of the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signalling in renal inflammation and fibrosis.

Mice with global cGAS deficiency or global or myeloid cell-specific STING deficiency or wild-type mice treated with RU.521, a selective cGAS inhibitor, were used to examine the role of cGAS-STING signalling in renal inflammation and fibrosis in a preclinical model of obstructive nephropathy in vivo. Bone marrow-derived macrophages were used to determine whether tubular epithelial cell-derived DNA can activate cGAS-STING signalling in vitro.

Following obstructive injury, cGAS-STING signalling was activated in the kidneys during the development of renal fibrosis. Mice with deficiency of cGAS or STING exhibited significantly less macrophage proinflammatory activation, myofibroblast formation, total collagen deposition, and extracellular matrix (ECM) protein production in the kidneys following obstructive injury. Pharmacological inhibition of cGAS with RU.521 reduced macrophage proinflammatory activation, suppressed myofibroblast formation, and attenuated kidney fibrosis following obstructive injury. Mechanistically, cGAS-STING signalling in macrophages is activated by double-stranded DNA released from damaged tubular epithelial cells, which induces inflammatory responses.

Our study identifies the cGAS-STING signalling pathway as a critical regulator of macrophage proinflammatory activation during the development of renal fibrosis. Therefore, inhibition of cGAS-STING signalling may represent a novel therapeutic strategy for CKD.

In a prior study, adoptive cell transfer (ACT) of Dexamethasone (DEX)-induced M2c macrophages with positive expression of MerTK receptor mitigated acute allograft rejection, which was observed in the presence of apoptotic lymphocytes, while simultaneously reducing MHC-II and CD8+ T cells in the recipients. However, there has been limited exploration of the properties of adoptive M2c cells, leaving their potential for other applications unclear. In this study, we aimed to characterize the transcriptome profile of DEX-induced MerTK+/high M2c macrophages. Notably, through the analysis of differentially expressed genes (DEGs), no significant pathway could be constructed from the upregulated DEGs. Only downregulated DEGs could facilitate KEGG construction, encompassing the role of DEX-induced MerTK+/high M2c in immune tolerance. The expression of T-cell activation, pro- and anti-inflammatory cytokines modulation, leukocyte recruitment and adjustment of MHC-I/II-related proteins were entirely diminished. Nonetheless, association of these traits suggests the potential of MerTK+/high M2c macrophages for use in ACT, particularly for autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, type-I diabetes mellitus, and AGE/RAGE signaling pathway in diabetic complications. In summary, the preference for downregulated gene expression profiles in DEX-induced MerTK+/high M2c macrophages affirms their potential for immunosuppressive adoptive cell therapy.

Chronic kidney disease (CKD) is a progressive condition characterized by the gradual loss of kidney function, leading to the accumulation of uremic toxins in the bloodstream. These toxins play a pivotal role in mediating vascular inflammation, a key contributor to the high cardiovascular morbidity and mortality observed in CKD patients. This review article explores the intricate mechanisms by which uremic toxins accelerate vascular inflammation. Macrophages, as versatile immune cells, are central to the inflammatory response. Evidence suggests that the uremic milieu influences macrophage biology. In this review article, we focus on the signaling through which uremic toxins, particularly indoxyl sulfate-an independent risk factor for cardiovascular complications in CKD patients, modulate macrophage activation and function, and how these changes contribute to vascular inflammation, leading to the increased cardiovascular risk. Investigation of such mechanisms provide molecular bases for the development of new therapies that retard the development of cardiovascular disorders in CKD patients.

Acute kidney injury (AKI) is a serious condition with high mortality in intensive care units and during vascular surgeries. Renal ischemia-reperfusion injury (IRI) significantly contributes to AKI. Preclinical studies have shown that myrtenal (Myrt) has anti-inflammatory and antioxidant properties. We hypothesized that Myrt might alleviate renal damage caused by IRI through the modulation of oxidative stress and inflammatory processes. This study aimed to investigate the renoprotective potential of Myrt against IRI using biochemical evaluations and histological examinations. Forty male Sprague Dawley rats were assigned to four groups: sham, IRI, Myrt40+IRI, and Myrt80+IRI. Animals received daily intraperitoneal injections of Myrt (40-80 mg/kg) or solvent for 9 days before surgery. The sham group underwent laparotomy, while the other groups had AKI induced via bilateral renal pedicle clamping for 45 min, followed by 24 h of reperfusion. Renal function was assessed by blood urea nitrogen (BUN), creatinine, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) levels. Inflammatory markers interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) were measured, along with oxidative stress parameters malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Renal damage was evaluated histopathologically using hematoxylin and eosin staining and apoptosis was assessed via caspase-3 immunohistochemistry. In the IRI group, serum BUN and creatinine levels were significantly higher than the sham group but were reduced by Myrt pretreatment (p < 0.05). IRI also led to significant increases in MDA, KIM-1, NGAL, IL-1β, and TNF-α in kidney tissue (p < 0.05), which were notably decreased by Myrt pretreatment (p < 0.05). Myrt also restored SOD and CAT enzyme activities and GSH levels reduced by IRI (p < 0.05). Histological analysis showed Myrt significantly alleviated renal tissue damage and reduced caspase-3 immunoreactivity due to IRI (p < 0.05). The findings suggest that Myrt has a protective effect against renal IRI.

Obesity is a rapidly growing health problem worldwide, affecting both adults and children and increasing the risk of chronic diseases such as type 2 diabetes, hypertension and cardiovascular disease (CVD). In addition, obesity is closely linked to chronic kidney disease (CKD) by either exacerbating diabetic complications or directly causing kidney damage. Obesity-related CKD is characterized by proteinuria, lipid accumulation, fibrosis and glomerulosclerosis, which can gradually impair kidney function. Among the immune cells of the innate and adaptive immune response involved in the pathogenesis of obesity-related diseases, macrophages play a crucial role in the inflammation associated with CKD. In obese individuals, macrophages enter a pro-inflammatory state known as M1 polarization, which contributes to chronic inflammation. This polarization promotes tissue damage, inflammation and fibrosis, leading to progressive loss of kidney function. In addition, macrophage-induced oxidative stress is a key feature of CKD as it also promotes cell damage and inflammation. Macrophages also contribute to insulin resistance in type 2 diabetes by releasing inflammatory molecules that impair glucose metabolism, complicating the management of diabetes in obese patients. Hypertension and atherosclerosis, which are often associated with obesity, also contribute to the progression of CKD via immune and inflammatory pathways. Macrophages influence blood pressure regulation and contribute to vascular inflammation, particularly via the renin-angiotensin system. In atherosclerosis, macrophages accumulate in arterial plaques, leading to chronic inflammation and plaque instability, which may increase the risk of CVD in CKD patients. This review focuses on the involvement of macrophages in CKD and highlights their role as a critical link between CKD and other pathologies. Targeting macrophage polarization and the ensuing macrophage-induced inflammation could be an effective therapeutic strategy for CKD and related diseases and improve outcomes for patients with obesity-related kidney disease.

Sterile inflammation has been increasingly recognized as a hallmark of non-infectious kidney diseases. Induction of pro-inflammatory cytokines in injured kidney tissue promotes infiltration of immune cells serving to clear cell debris and facilitate tissue repair. However, excessive or prolonged inflammatory response has been associated with immune-mediated tissue damage, nephron loss, and development of renal fibrosis. Interleukin 6 (IL-6) is a cytokine with pleiotropic effects including a major role in inflammation. IL-6 signals either via membrane-bound (classic signaling) or soluble receptor forms (trans-signaling) thus affecting distinct cell types and eliciting various metabolic, cytoprotective, or pro-inflammatory reactions. Antibodies neutralizing IL-6 or its receptor have been developed for therapy of autoimmune and chronic non-renal inflammatory diseases. Small molecule inhibitors of Janus kinases acting downstream of the IL-6 receptor, as well as recombinant soluble glycoprotein 130 variants suppressing the IL-6 trans-signaling add to the available therapeutic options. Animal data and accumulating clinical experience strongly suggest that suppression of IL-6 signaling pathways bears therapeutic potential in acute and chronic kidney diseases. The present work analyses the renoprotective potential of clinically relevant IL-6 signaling inhibitors in acute kidney injury, chronic kidney disease, and kidney transplantation with focus on current achievements and future prospects.

Over the last decades, the human species has seen an increase in the incidence of pathologies linked to the genitourinary tract. Observations in animals have allowed us to link these increases, at least in part, to changes in the environment and, in particular, to an increasing presence of endocrine disruptors. These can be physical agents, such as light or heat; natural products, such as phytoestrogens; or chemicals produced by humans. Endocrine disruptors may interfere with the signaling pathways mediated by the endocrine system, particularly those linked to sex hormones. These factors and their general effects are presented before focusing on the male and female genitourinary tracts by describing their anatomy, development, and pathologies, including bladder and prostate cancer.

Background: Hypertension is a major cause of mortality worldwide. The kidneys play a crucial role in regulating blood pressure and fluid volume. The relationship between the kidneys and hypertension is complex, involving factors such as the renin-angiotensin system, oxidative stress, and inflammation. This study aims to assess the levels of inflammatory markers, oxidative stress, and metabolic factors in the kidneys, focusing on their potential role in early renal damage and their association with the development of hypertension. Methods: This study was designed to compare the levels of selected inflammatory markers, e.g., interleukins, tumor necrosis factor-α (TNF-α), transforming growth factor, and serine/threonine-protein (mTOR); oxidative stress markers such as malondialdehyde, sulfhydryl group, and glucose (GLC); and metabolic markers among other enzymes, such as alanine transaminase (ALT), aspartate transaminase (AST), hexokinase II (HK-II), and hypoxia-inducible factor-1α (HIF-1α), as well as creatinine in the kidneys of spontaneously hypertensive rats (SHR/NCrl, n = 12) and Wistar Kyoto rats (WKY/NCrl, n = 12). Both juvenile (5 weeks old) and maturing (10 weeks old) specimens were examined using spectrophotometric methods, e.g., ELISA. Results: Juvenile SHRs exhibited reduced renal levels of all studied cytokines and chemokines, with lower oxidative stress and deficits in the mTOR and HK-II levels compared to the age-matched WKYs. Maturing SHRs showed increased renal levels of interleukin-1β (IL-1β), IL-6, IL-18, and TNF-α, alongside elevated carbonyl stress and increased HIF-1α as opposed to their control peers. The levels of all other studied markers were normalized in these animals, except for ALT (increased), ALP, and GLC (both reduced). Conclusions: This study underscores the significant impact of inflammatory, oxidative stress, and metabolic marker changes on renal function. Juvenile SHRs display lower marker levels, indicating an immature immune response and potential subclinical kidney damage that may contribute to hypertension development. In contrast, mature SHRs exhibit chronic inflammation, oxidative dysregulation, and metabolic disturbances, suggesting cellular damage. These changes create a feedback loop that worsens kidney function and accelerates hypertension progression, highlighting the kidneys' crucial role in both initiating and exacerbating this condition.

Rhubarb (Rheum palmatum L.) and astragalus (Radix astragali) find widespread used in clinical formulations for treating chronic kidney disease (CKD). Notably, the key active components, total rhubarb anthraquinone (TRA) and total astragalus saponin (TAS), exhibit superiority over rhubarb and astragalus in terms of their clear composition, stability, quality control, small dosage, and efficacy for disease treatment. Additionally, astragalus polysaccharides (APS) significantly contribute to the treatment of renal fibrosis by modulating the gut microbiota. However, due to differences in the biopharmaceutical properties of these components, achieving synergistic effects remains challenging. This study aims to develop combined pellets (CPs) and evaluate the potential effect on unilateral ureteral obstruction (UUO)-induced renal fibrosis.

The CPs pellets were obtained by combining TRA/TAS-loaded SNEDDS pellets and APS-loaded pellets, prepared using the fluidized bed coating process. The prepared pellets underwent evaluation for morphology, bulk density, hardness, and flowing property. Moreover, the in vitro release of the payloads was evaluated with the CHP Type I method. Furthermore, the unilateral ureteral obstruction (UUO) model was utilized to investigate the potential effects of CPs pellets on renal fibrosis and their contribution to gut microbiota modulation.

The ex-vivo study demonstrated that the developed CPs pellets not only improved the dissolution of TRA and TAS but also delivered TRA/TAS and APS spatiotemporally to the appropriate site along the gastrointestinal tract. In an animal model of renal fibrosis (UUO rats), oral administration of the CPs ameliorated kidney histological pathology, reduced collagen deposition, and decreased the levels of inflammatory cytokines. The CPs also restored the disturbed gut microbiota induced by UUO surgery and protected the intestinal barrier.

The developed CPs pellets represent a promising strategy for efficiently delivering active components in traditional Chinese medicine formulas, offering an effective approach for treating CKD.

In this editorial, we comment on the article by Wu et al published "MicroRNA-630 alleviates inflammatory reactions in rats with diabetic kidney disease by targeting toll-like receptor 4". Diabetic kidney disease (DKD) stands as a significant complication occurring from diabetes mellitus, which contributes substantially to the morbidity and mortality rates worldwide. Renal tubular epithelial cell da-mage, often accompanied by inflammatory responses and mesenchymal trans-differentiation, plays a pivotal role in the progression of DKD. Despite extensive research, the intricate molecular mechanisms underlying these processes remain to be determined. Wu et al remarkable work identifies microRNA-630 (miR-630) as an emerging potential regulator of cell migration, apoptosis, and autophagy, prompting investigation into its association with DKD pathogenesis. This study endeavors to elucidate the impact of miR-630 on TEC injury and the inflammatory response in DKD rats. The role of miR-630 in human DKD will be of interest for future studies.

The incidence of severe acute kidney injury (AKI) is considerably high worldwide. A previous study showed that gut microbial dysbiosis was a hallmark of AKI in mice. Whether the probiotic Lactobacillus casei strain Shirota (LcS) plays a role in kidney disease, particularly AKI, remains unclear.

To investigate the effects of LcS on kidney injury, tubule-specific conditional von Hippel-Lindau gene-knockout C57BL/6 mice (Vhlhdel/del mice) were supplemented without (Ctrl) or with probiotics (LcS) in Experiment 1, and their lifespan was monitored. Additionally, the Vhlhdel/+ mice were supplemented without (Ctrl and AA) or with probiotics (LcS and LcS + AA) in Experiment 2. Probiotic LcS (1 × 109 colony-forming units) was supplemented once daily. After 4 weeks of LcS supplementation, AA and LcS + AA mice were administered aristolochic acid (AA; 4 mg/kg body weight/day)-containing purified diet for 2 weeks to induce AA nephropathy before sacrifice.

Supplementation of LcS significantly prolonged the lifespan of Vhlhdel/del mice, suggesting a potential renal protective effect. AA induced-nephropathy increased not only the indicators of renal dysfunction and injury, including urinary protein and kidney injury molecule (KIM)-1, serum blood urea nitrogen (BUN) and creatinine, but also serum interleukin (IL)-6 levels, renal macrophage infiltrations, and pathological lesions in Vhlhdel/+ mice. LcS supplementation significantly reduced urinary protein and KIM-1 levels, serum BUN and IL-6 levels, and renal M1 macrophages, tissue lesions, and injury scores. We also found that LcS maintained gut integrity under AA induction and increased intestinal lamina propria dendritic cells. Furthermore, LcS significantly reduced pro-inflammatory IL-17A and upregulated anti-inflammatory IL-10 production by immune cells from intestinal Peyer's patches (PP) or mesenteric lymph nodes (MLN), and significantly increased IL-10 and reduced IL-6 production by splenocytes.

Prior supplementation with probiotic LcS significantly alleviated the severity of renal injury. This renal protective effect was partially associated with the enhancements of intestinal and systemic anti-inflammatory immune responses, suggesting that LcS-induced immunoregulation might contribute to its renal protective effects.

To assess the effect of Amorphophallus campanulatus tuber (Ac) extract in the protection of diabetic nephropathy in streptozotocin (STZ) induced diabetic nephropathy (DN) rat model.

Diabetes was induced with STZ (60 mg/kg, i.p.), and DN was confirmed after six weeks of STZ administration with the estimation of kidney function test. Further rats were treated with Ac 250 and 500 mg/kg p.o. for next four week. Oxidative stress and level of inflammatory cytokines were estimated in the kidney tissue of DN rats. Histopathology of kidney tissue was performed using hematoxylin and eosin staining.

There was improvement in the body weight of Ac treated groups than DN group of rats. Blood glucose level was observed to be reduced in Ac treated groups than DN group on 42nd and 70th day of protocol. Treatment with Ac ameliorated the altered level of kidney function tests (creatinine and BUN), enzymes of liver function (aspartate aminotransferase and alanine aminotransferase), and lipid profile in the serum of DN rats. Oxidative stress parameters (malondialdehyde and reactive oxygen species enhances and reduction in the level of glutathione and superoxide dismutase) and inflammatory cytokines such as interleukin-6, tumour necrosis factor-α, and monocyte chemoattractant protein-1 reduces in the tissue of Ac treated group than DN group. Treatment with Ac also attenuates the altered histopathological changes in the kidney tissue of DN rats.

The report suggests that Ac protects renal injury in DN rats by regulating inflammatory cytokines and oxidative stress.

Identifying the biomarkers associated with new-onset glomerular filtration rate (GFR) decrease in an initially healthy population could offer a better understanding of kidney function decline and help improving patient management.

Here we described the proteomic and transcriptomic footprints associated with new-onset kidney function decline in an initially healthy and well-characterized population with a 20-year follow-up. This study was based on 1087 individuals from the familial longitudinal Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) cohort who attended both visit 1 (from 1993 to 1995) and visit 4 (from 2011 to 2016). New-onset kidney function decline was approached both in quantitative (GFR slope for each individual) and qualitative (defined as a decrease in GFR of >15 ml/min/1.7 m2) ways. We analysed associations of 445 proteins measured both at visit 1 and visit 4 using Olink Proseek® panels and 119 765 genes expressions measured at visit 4 with GFR decline. Associations were assessed using multivariable models. The Bonferroni correction was applied.

We found several proteins (including PLC, placental growth factor (PGF), members of the tumour necrosis factor receptor superfamily), genes (including CCL18, SESN3), and a newly discovered miRNA-mRNA pair (MIR1205-DNAJC6) to be independently associated with new-onset kidney function decline. Complex network analysis highlighted both extracellular matrix and cardiovascular remodelling (since visit 1) as well as inflammation (at visit 4) as key features of early GFR decrease.

These findings lay the foundation to further assess whether the proteins and genes herein identified may represent potential biomarkers or therapeutic targets to prevent renal function impairment.

Acute tubular injury (ATI) is a common diagnosis on renal biopsy. There are no accepted parameters to assess the severity of injury or predict recovery. An objective histologic grading system would be of immense value in clinical practice. The macrophage response to injury involves the MI phenotype which is proinflammatory and M2 which is prorepair. The study of these macrophages could aid in studying the severity and the recovery.

A total of 58 native kidney biopsies with features of ATI and a minimum follow-up of 12 weeks were graded into mild, moderate and severe, using scores for simplification, sloughing, and mitosis. These scores and the density of macrophages stained with CD68, CD163, and HLA-DR were correlated with serum creatinine at presentation and with recovery. The effect of chronicity index as measured by glomerulosclerosis, tubular atrophy, and interstitial fibrosis and of co-morbidities of age, hypertension, and diabetes on the recovery pattern was also studied.

All three histologic scores and the grades of ATI showed positive correlation with the serum creatinine level. The densities of CD 68 + and CD163 + macrophages also showed a significant correlation with serum creatinine level. However, none of these these histological features nor the macrophage densities predicted clinical recovery. Age >60 years, hypertension, diabetes, and chronicity score on biopsy were indicators of partial and delayed recovery.

The histopathological semiquantitative scoring system can be used routinely to grade ATI. However none of the studied parameters predicted recovery.

Macrophages (Mφ) autophagy is a pivotal contributor to inflammation-related diseases. However, the mechanistic details of its direct role in acute kidney injury (AKI) were unclear. Here, we show that Mφ promote AKI progression via crosstalk with tubular epithelial cells (TECs), and autophagy of Mφ was activated and then inhibited in cisplatin-induced AKI mice. Mφ-specific depletion of ATG7 (Atg7Δmye) aggravated kidney injury in AKI mice, which was associated with tubulointerstitial inflammation. Moreover, Mφ-derived exosomes from Atg7Δmye mice impaired TEC mitochondria in vitro, which may be attributable to miR-195a-5p enrichment in exosomes and its interaction with SIRT3 in TECs. Consistently, either miR-195a-5p inhibition or SIRT3 overexpression improved mitochondrial bioenergetics and renal function in vivo. Finally, adoptive transfer of Mφ from AKI mice to Mφ-depleted mice promotes the kidney injury response to cisplatin, which is alleviated when Mφ autophagy is activated with trehalose. We conclude that exosomal miR-195a-5p mediate the communication between autophagy-deficient Mφ and TECs, leading to impaired mitochondrial biogenetic in TECs and subsequent exacerbation of kidney injury in AKI mice via miR-195a-5p-SIRT3 axis.

Macrophages are exceptionally diversified cell types and perform unique features and functions when exposed to different stimuli within the specific microenvironment of various kidney diseases. In instances of kidney tissue necrosis or infection, specific patterns associated with damage or pathogens prompt the development of pro-inflammatory macrophages (M1). These M1 macrophages contribute to exacerbating tissue damage, inflammation, and eventual fibrosis. Conversely, anti-inflammatory macrophages (M2) arise in the same circumstances, contributing to kidney repair and regeneration processes. Impaired tissue repair causes fibrosis, and hence macrophages play a protective and pathogenic role. In response to harmful stimuli within the body, inflammasomes, complex assemblies of multiple proteins, assume a pivotal function in innate immunity. The initiation of inflammasomes triggers the activation of caspase 1, which in turn facilitates the maturation of cytokines, inflammation, and cell death. Macrophages in the kidneys possess the complete elements of the NLRP3 inflammasome, including NLRP3, ASC, and pro-caspase-1. When the NLRP3 inflammasomes are activated, it triggers the activation of caspase-1, resulting in the release of mature proinflammatory cytokines (IL)-1β and IL-18 and cleavage of Gasdermin D (GSDMD). This activation process therefore then induces pyroptosis, leading to renal inflammation, cell death, and renal dysfunction. The NLRP3-ASC-caspase-1-IL-1β-IL-18 pathway has been identified as a factor in the development of the pathophysiology of numerous kidney diseases. In this review, we explore current progress in understanding macrophage behavior concerning inflammation, injury, and fibrosis in kidneys. Emphasizing the pivotal role of activated macrophages in both the advancement and recovery phases of renal diseases, the article delves into potential strategies to modify macrophage functionality and it also discusses emerging approaches to selectively target NLRP3 inflammasomes and their signaling components within the kidney, aiming to facilitate the healing process in kidney diseases.

In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs).

Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury.

Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury.

Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

To examine the correlation between SIRI and the probability of cardiovascular mortality as well as all-cause mortality in individuals with chronic kidney disease.

A cohort of 3,262 participants from the US National Health and Nutrition Examination Survey (NHANES) database were included in the study. We categorized participants into five groups based on the stage of chronic kidney disease. A weighted Cox regression model was applied to assess the relationship between SIRI and mortality. Subgroup analyses, Kaplan-Meier survival curves, and ROC curves were conducted. Additionally, restricted cubic spline analysis was employed to elucidate the detailed association between SIRI and hazard ratio (HR).

This study included a cohort of 3,262 individuals, of whom 1,535 were male (weighted proportion: 42%), and 2,216 were aged 60 or above (weighted proportion: 59%). Following adjustments for covariates like age, sex, race, and education, elevated SIRI remained a significant independent risk factor for cardiovascular mortality (HR=2.50, 95%CI: 1.62-3.84, p<0.001) and all-cause mortality (HR=3.02, 95%CI: 2.03-4.51, p<0.001) in CKD patients. The restricted cubic spline analysis indicated a nonlinear relationship between SIRI and cardiovascular mortality, with SIRI>1.2 identified as an independent risk factor for cardiovascular mortality in CKD patients.

Heightened SIRI independently poses a risk for both all-cause and cardiovascular mortality in chronic kidney disease patients, with potentially heightened significance in the early stages (Stage I to Stage III) of chronic kidney disease.

Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.

Chronic kidney disease (CKD) is a public health problem driven by myofibroblast accumulation, leading to interstitial fibrosis. Heterogeneity is a recently recognized characteristic in kidney fibroblasts in CKD, but the role of different populations is still unclear. Here, we characterize a proinflammatory fibroblast population (named CXCL-iFibro), which corresponds to an early state of myofibroblast differentiation in CKD. We demonstrate that CXCL-iFibro co-localize with macrophages in the kidney and participate in their attraction, accumulation, and switch into FOLR2+ macrophages from early CKD stages on. In vitro, macrophages promote the switch of CXCL-iFibro into ECM-secreting myofibroblasts through a WNT/β-catenin-dependent pathway, thereby suggesting a reciprocal crosstalk between these populations of fibroblasts and macrophages. Finally, the detection of CXCL-iFibro at early stages of CKD is predictive of poor patient prognosis, which shows that the CXCL-iFibro population is an early player in CKD progression and demonstrates the clinical relevance of our findings.

The Monocyte chemoattractant protein-1 (MCP-1), also referred to as chemokine ligand 2 (CCL2), belongs to the extensive chemokine family and serves as a crucial mediator of innate immunity and tissue inflammation. It has a notable impact on inflammatory conditions affecting the kidneys. Upon binding to its receptor, MCP-1 can induce lymphocytes and NK cells' homing, migration, activation, differentiation, and development while promoting monocytes' and macrophages' infiltration, thereby facilitating kidney disease-related inflammation. As a biomarker for kidney disease, MCP-1 has made notable advancements in primary kidney diseases such as crescentic glomerulonephritis, chronic glomerulonephritis, primary glomerulopathy, idiopathic proteinuria glomerulopathy, acute kidney injury; secondary kidney diseases like diabetic nephropathy and lupus nephritis; hereditary kidney diseases including autosomal dominant polycystic kidney disease and sickle cell kidney disease. MCP-1 not only predicts the occurrence, progression, prognosis of the disease but is also closely associated with the severity and stage of nephropathy. When renal tissue is stimulated or experiences significant damage, the expression of MCP-1 increases, demonstrating a direct correlation with the severity of renal injury.

Recent advancements in cancer treatment have explored a variety of approaches to address the needs of patients. Recently, immunotherapy has evolved as an efficacious treatment for various cancers resistant to conventional therapies. Hence, significant milestones in immunotherapy were achieved clinically in a large subset of cancer patients. Unfortunately, some cancer types do not respond to treatment, and among the responsive cancers, some patients remain unresponsive to treatment. Consequently, there is a critical need to examine the mechanisms of immune resistance and devise strategies to target immune suppressor cells or factors, thereby allowing for tumor sensitivity to immune cytotoxic cells. M2 macrophages, also known as tumor-associated macrophages (TAMs), are of interest due to their role in suppressing the immune system and influencing antitumor immune responses through modulating T cell activity and immune checkpoint expression. TAMs are associated with signaling pathways that modulate the tumor microenvironment (TME), contributing to immune evasion. One approach targets TAMs, focusing on preventing the polarization of M1 macrophages into the protumoral M2 phenotype. Other strategies focus on direct or indirect targeting of M2 macrophages through understanding the interaction of TAMs with immune factors or signaling pathways. Clinically, biomarkers associated with TAMs' immune resistance in cancer patients have been identified, opening avenues for intervention using pharmacological agents or immunotherapeutic approaches. Ultimately, these multifaceted approaches are promising in overcoming immune resistance and improving cancer treatment outcomes.

Acute intermittent porphyria (AIP) is an inherited metabolic disorder associated with complications including kidney failure and hepatocellular carcinoma, probably caused by elevations in the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA). This study explored differences in modern biomarkers for renal and hepatic damage between AIP patients and controls. Urine PBG testing, kidney injury panels, and liver injury panels, including both routine and modern biomarkers, were performed on plasma and urine samples from AIP cases and matched controls (50 and 48 matched pairs, respectively). Regarding the participants' plasma, the AIP cases had elevated kidney injury marker-1 (KIM-1, p = 0.0002), fatty acid-binding protein-1 (FABP-1, p = 0.04), and α-glutathione S-transferase (α-GST, p = 0.001) compared to the matched controls. The AIP cases with high PBG had increased FABP-1 levels in their plasma and urine compared to those with low PBG. In the AIP cases, KIM-1 correlated positively with PBG, CXCL10, CCL2, and TCC, and the liver marker α-GST correlated positively with IL-13, CCL2, and CCL4 (all p < 0.05). In conclusion, KIM-1, FABP-1, and α-GST could represent potential early indicators of renal and hepatic damage in AIP, demonstrating associations with porphyrin precursors and inflammatory markers.

Inflammation has been associated with renal diseases. The Interferon Regulatory Factor (IRF)-5 is a key transcription factor in the pro-inflammatory polarization of M1-like macrophages. GWAS have reported that the IRF5 locus is associated with autoimmune diseases and with the estimated glomerular filtration rate (eGFR). We study whether allelic variations in IRF5 are associated with the incidence of chronic kidney disease (CKD) in a general population. We genotyped eleven IRF5 SNPs in the French D.E.S.I.R. cohort from the general population (n = 4820). Associations of SNPs with baseline renal parameters were assessed. Data were analyzed for three endpoints during a 9-year follow-up, incidence of:at least stage 3 CKD, the KDIGO criterion "certain drop in eGFR", and incidence of micro/macro albuminuria. In the cross-sectional analysis, rs10954213 and rs10954214 were associated with eGFR and rs1874328 with urinary albumin/creatinine ratio (ACR). Rs3807306, rs11761199, rs78658945, rs1874328, rs10954213 and rs11770589 were associated with the incidence of stage 3 CKD in multi-adjusted models. Rs4731532, rs3807306, and rs11761199 were associated with the incidence of CKD defined by the KDIGO. Rs4731532, rs3807306, rs11761199 and rs79288514 were associated with the incidence of micro/macro albuminuria. Our results support the hypothesis of the importance of IRF5 mediated macrophage polarization in the etiology of CKD.

Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown beneficial effects on different experimental preclinical diseases, mainly by inhibiting proliferative and inflammatory responses. However the effect of BET inhibition on peritoneal damage has not been studied. To this aim, we have evaluated the effects of treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 decreased gene overexpression of proinflammatory and profibrotic markers, together with an inhibition of the nuclear factor-κB (NF-κB) pathway. Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To corroborate the in vivo findings, we evaluated the effects of the BET inhibitor JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A cell line. JQ1 inhibited tumor necrosis factor-α (TNF-α)-induced proinflammatory gene upregulation and restored MMT phenotype changes, together with the downmodulation of oxidative stress. Taken together, these results suggest that BET inhibitors may be a potential therapeutic option to ameliorate peritoneal damage.

Previously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess the effects of UAB126 on the progression of diabetic retinopathy (DR) in rodent models of type 1 diabetes (T1D), streptozotocin-induced, and type 2 diabetes (T2D), in db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar and the expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR.

Obesity is a serious chronic disease and an independent risk factor for the new onset and progression of chronic kidney disease (CKD). CKD prevalence is expected to increase, at least partly due to the continuous rise in the prevalence of obesity. The concept of obesity-related kidney disease (OKD) has been introduced to describe the still incompletely understood interplay between obesity, CKD, and other cardiometabolic conditions, including risk factors for OKD and cardiovascular disease, such as diabetes and hypertension. Current therapeutics target obesity and CKD individually. Non-pharmacological interventions play a major part, but the efficacy and clinical applicability of lifestyle changes and metabolic surgery remain debatable, because the strategies do not benefit everyone, and it remains questionable whether lifestyle changes can be sustained in the long term. Pharmacological interventions, such as sodium-glucose co-transporter 2 inhibitors and the non-steroidal mineralocorticoid receptor antagonist finerenone, provide kidney protection but have limited or no impact on body weight. Medicines based on glucagon-like peptide-1 (GLP-1) induce clinically relevant weight loss and may also offer kidney benefits. An urgent medical need remains for investigations to better understand the intertwined pathophysiologies in OKD, paving the way for the best possible therapeutic strategies in this increasingly prevalent disease complex.

Management of diabetic kidney disease (DKD) has evolved in parallel with our growing understanding of the multiple interrelated pathophysiological mechanisms that involve hemodynamic, metabolic, and inflammatory pathways. These pathways and others play a vital role in the initiation and progression of DKD. Since its initial discovery, the blockade of the renin-angiotensin system has remained a cornerstone of DKD management, leaving a large component of residual risk to be dealt with. The advent of sodium-glucose cotransporter 2 inhibitors followed by nonsteroidal mineralocorticoid receptor antagonists and, to some extent, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has ushered in a resounding paradigm shift that supports a pillared approach in maximizing treatment to reduce outcomes. This pillared approach is like that derived from the approach to heart failure treatment. The approach mandates that all agents that have been shown in clinical trials to reduce cardiovascular outcomes and/or mortality to a greater extent than a single drug class alone should be used in combination. In this way, each drug class focuses on a specific aspect of the disease's pathophysiology. Thus, in heart failure, β-blockers, sacubitril/valsartan, a mineralocorticoid receptor antagonist, and a diuretic are used together. In this article, we review the evolution of the pillar concept of therapy as it applies to DKD and discuss how it should be used based on the outcome evidence. We also discuss the exciting possibility that GLP-1 RAs may be an additional pillar in the quest to further slow kidney disease progression in diabetes.

Obesity is a significant risk factor for chronic kidney disease (CKD). This study aimed to evaluate the impact of obesity on the development of kidney fibrosis in a model of cafeteria diet rats undergoing 5/6th nephrectomy (SNx). Collagen 1, 3, and 4 expression, adipocyte size, macrophage number, and the expression of 30 adipokines were determined. Collagen 1 expression in kidney tissue was increased in Standard-SNx and Cafeteria-SNx (7.1 ± 0.6% and 8.9 ± 0.9 tissue area, respectively). Renal expression of collagen 3 and 4 was significantly increased (p < 0.05) in Cafeteria-SNx (8.6 ± 1.5 and 10.9 ± 1.9% tissue area, respectively) compared to Cafeteria (5.2 ± 0.5 and 6.3 ± 0.6% tissue area, respectively). Adipocyte size in eWAT was significantly increased by the cafeteria diet. In Cafeteria-SNx, we observed a significant increase in macrophage number in the kidney (p = 0.01) and a consistent tendency in eWAT. The adipokine level was higher in the Cafeteria groups. Interleukin 11, dipeptidyl peptidase 4, and serpin 1 were increased in Cafeteria-SNx. In the kidney, collagen 3 and 4 expressions and the number of macrophages were increased in Cafeteria-SNx, suggesting an exacerbation by preexisting obesity of CKD-induced renal inflammation and fibrosis. IL11, DPP4, and serpin 1 can act directly on fibrosis and participate in the observed worsening CKD.

Some chemoattractants and leukocytes such as M1 and M2 macrophages are known to be involved in the development of glomerulosclerosis during diabetic nephropathy (DN). In the course of diabetes, an altered and defective cellular metabolism leads to the increase in adenosine levels, and thus to changes in the polarity (M1/M2) of macrophages. MRS1754, a selective antagonist of the A2B adenosine receptor (A2BAR), attenuated glomerulosclerosis and decreased macrophage-myofibroblast transition in DN rats. Therefore, we aimed to investigate the effect of MRS1754 on the glomerular expression/secretion of chemoattractants, the intraglomerular infiltration of leukocytes, and macrophage polarity in DN rats. Kidneys/glomeruli of non-diabetic, DN, and MRS1754-treated DN rats were processed for transcriptomic analysis, immunohistopathology, ELISA, and in vitro macrophage migration assays. The transcriptomic analysis identified an upregulation of transcripts and pathways related to the immune system in the glomeruli of DN rats, which was attenuated using MRS1754. The antagonism of the A2BAR decreased glomerular expression/secretion of chemoattractants (CCL2, CCL3, CCL6, and CCL21), the infiltration of macrophages, and their polarization to M2 in DN rats. The in vitro macrophages migration induced by conditioned-medium of DN glomeruli was significantly decreased using neutralizing antibodies against CCL2, CCL3, and CCL21. We concluded that the pharmacological blockade of the A2BAR decreases the transcriptional expression of genes/pathways related to the immune response, protein expression/secretion of chemoattractants, as well as the infiltration of macrophages and their polarization toward the M2 phenotype in the glomeruli of DN rats, suggesting a new mechanism implicated in the antifibrotic effect of MRS1754.

Vascular in situ tissue engineering encompasses a single-step approach with a wide adaptive potential and true off-the-shelf availability for vascular grafts. However, a synchronized balance between breakdown of the scaffold material and neo-tissue formation is essential. Chronic kidney disease (CKD) may influence this balance, lowering the usability of these grafts for vascular access in end-stage CKD patients on dialysis. We aimed to investigate the effects of CKD on in vivo scaffold breakdown and tissue formation in grafts made of electrospun, modular, supramolecular polycarbonate with ureido-pyrimidinone moieties (PC-UPy). We implanted PC-UPy aortic interposition grafts (n = 40) in a rat 5/6th nephrectomy model that mimics systemic conditions in human CKD patients. We studied patency, mechanical stability, extracellular matrix (ECM) components, total cellularity, vascular tissue formation, and vascular calcification in CKD and healthy rats at 2, 4, 8, and 12 weeks post-implantation. Our study shows successful in vivo application of a slow-degrading small-diameter vascular graft that supports adequate in situ vascular tissue formation. Despite systemic inflammation associated with CKD, no influence of CKD on patency (Sham: 95% vs CKD: 100%), mechanical stability, ECM formation (Sirius red⁺, Sham 16.5% vs CKD 25.0%-p:0.83), tissue composition, and immune cell infiltration was found. We did find a limited increase in vascular calcification at 12 weeks (Sham 0.08% vs CKD 0.80%-p:0.02) in grafts implanted in CKD animals. However, this was not associated with increased stiffness in the explants. Our findings suggest that disease-specific graft design may not be necessary for use in CKD patients on dialysis.

Induced pluripotent stem cells (iPSCs) have been the focus of cellular therapy studies. The use of iPSCs in regenerative medicine is limited by their tumorigenic potential. This study sought to determine whether iPSCs-derived podocytes attenuate acute kidney injury (AKI) and the molecular mechanism. Inoculation of iPSCs-podocytes significantly promoted the repair of kidney injury in AKI mice, reduced the levels of kidney injury factors Scr, BUN, and urinary NAG, and alleviated the inflammatory response. Histological analysis revealed a significant increase in the number of M2 macrophages and a significant decrease in M1 macrophages in the kidney tissues. Subsequently, the genes and signaling pathways that may be associated with kidney injury repair in mice were analyzed by RNA-seq and bioinformatics prediction. The polarization of M2 macrophages was promoted by MAF bZIP transcription factor B (Mafb)-mediated activation of C-C motif chemokine receptor 5 (Ccr5) and nicotinamide phosphoribosyltransferase (Nampt) signaling pathway. Taken together, these results show that iPSCs-podocytes depend on Mafb to activate the Nampt signaling pathway through transcriptional activation of Ccr5, thereby promoting the repair of AKI caused by ischemia-reperfusion.

Macrophages play critical roles in mediating and resolving tissue injury as well as tissue remodeling during cardiorenal disease. Altered immunometabolism, particularly macrophage metabolism, is a critical underlying mechanism of immune dysfunction and inflammation, particularly in individuals with underlying metabolic abnormalities. In this review, we discuss the critical roles of macrophages in cardiac and renal injury and disease. We also highlight the roles of macrophage metabolism and discuss metabolic abnormalities, such as obesity and diabetes, which may impair normal macrophage metabolism and thus predispose individuals to cardiorenal inflammation and injury. As the roles of macrophage glucose and fatty acid metabolism have been extensively discussed elsewhere, we focus on the roles of alternative fuels, such as lactate and ketones, which play underappreciated roles during cardiac and renal injury and heavily influence macrophage phenotypes.

Emamectin benzoate (EMB) as one of the typical biological pesticides has a wide range of applications in agriculture. However, the immune toxic effects of EMB in human received limited attention. In our study, THP-1 macrophage as an in vitro model was used to evaluate immune functions exposed to EMB. We observed that EMB inhibited phagocytic activity and respiratory burst capacity of macrophages without inducing cellular toxicity, implying the potential immunosuppression. Besides, EMB disturbed the cytokines balance embodied in the increase of TNF-α, IL-1β, IL-6, CCL27, CXCL8 mRNA expression and the decrease of IL-4, IL-13, IL-10 mRNA expression. EMB could exhibit pro-inflammatory responses in macrophages and promote the conversion of macrophages to M1 phenotype. Moreover, NF-κB pathway involved in regulating immune function from KEGG pathway analysis. EMB exposure could activate the NF-κB pathway in THP-1 macrophages by exploring the critical proteins. This research provided insights on immunotoxicity evaluation and clarified EMB-induced immunotoxicity was related to NF-κB pathway activation.

Nanocellulose application has been increasing owing to its appealing physicochemical properties. Monitoring of the crystallinity, surface topography, and reactivity of this high-aspect-ratio nanomaterial is crucial for efficient tissue engineering. Controlling macrophage polarization phenotype remains a challenge in regenerative medicine and tissue engineering. Herein, we monitored the effects of shape-regulated (rod and spherical) nanocellulose on the macrophage modulatory potential of RAW 246.7 cells in vitro. Spherical nanocellulose (s-NC) exhibited higher thermal stability and biocompatibility than rod nanocellulose. Macrophage polarization was profoundly affected by nanocellulose topography and incubation period. M2 polarization was observed in vitro after 1 day of treatment with s-NC, followed by M1 polarization after treatment for longer periods. Transcriptome analysis similarly revealed that M1 polarization was dominant after 1 day h of incubation with both nanocellulose types. These findings demonstrate that macrophage polarization can be controlled by selecting suitable nanocellulose shape and incubation time for desired applications.