A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury

Privratsky, Jamie R.; Ide, Shintaro; Chen, Yanting; Kitai, Hiroki; Ren, Jiafa; Fradin, Hélène; Lu, Xiaohan; Souma, Tomokazu; Crowley, Steven D.

doi:10.1016/j.kint.2022.10.008

Cited by 21 publications

(12 citation statements)

References 54 publications

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“…Effector immunocytes, such as macrophages, play an essential modulatory role during septic organ damage (37,38). Under physiological conditions, LpMs in the gut gradually achieve a tissue-resident phenotype with a high proportion of inflammatory anergy, often referred to as M2 macrophages (39).…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV modulates gut macrophages M1/M2 polarization by reshaping gut microbiota and SCFA in sepsis

Yang,

Xie,

Cao

et al. 2023

Shock

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M1 macrophage-mediated inflammation is critical in sepsis. We previously found protective role of Astragaloside IV (AS-IV) in sepsis-associated gut impairment, whose specific mechanism remains unknown. Gut microbiota modulates gut homeostatic balance to avoid excessive inflammation. Here, we aimed to investigate effects of AS-IV on gut macrophages polarization and potential roles of gut microbiota and short chain fatty acids (SCFA) in septic gut damage. Mice were pre-treated by AS-IV gavage for 7 days before cecal ligation and puncture (CLP). M1 polarization of gut lamina propria macrophages (LpMs) was promoted by CLP, accompanied by abnormal cytokines release and intestinal barrier dysfunction. NLRP3 inflammasome was activated in M1 LpMs. 16S rRNA sequencing demonstrated gut microbiota imbalance. The levels of acetate, propionate and butyrate in fecal samples decreased. Notably, AS-IV reversed LpMs M1/M2 polarization, lightened gut inflammation and barrier injury, reduced NLRP3 inflammasome expression in LpMs, restored the diversity of gut microbiome and increased butyrate levels. Similarly, these benefits were mimicked by fecal microbiota transplantation (FMT) or exogenous butyrate supplementation. In Caco-2 and THP-1 co-cultured model, lipopolysaccharide (LPS) and interferon-γ (IFN-γ) caused THP-1 M1 polarization, Caco-2 barrier impairment, abnormal cytokines release and high NLRP3 inflammasome expression in THP-1 cells, all of which were mitigated by butyrate administration. However, these protective effects of butyrate were abrogated by NLRP3 gene overexpression in THP-1. In conclusion, AS-IV can ameliorate sepsis-induced gut inflammation and barrier dysfunction by modulating M1/M2 polarization of gut macrophages, whose underlying mechanism may be restoring gut microbiome and SCFA to restrain NLRP3 inflammasome activation.

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Section: Discussionmentioning

confidence: 99%

Astragaloside IV modulates gut macrophages M1/M2 polarization by reshaping gut microbiota and SCFA in sepsis

Yang,

Xie,

Cao

et al. 2023

Shock

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“…Kidney digestion and cell isolation. Our scRNAseq cell isolation protocol has been previously described ( Ide et al, 2021 ; Privratsky et al, 2023 ). Mice were perfused with ice-cold PBS via cardiac puncture after which the kidneys were harvested.…”

Section: Methodsmentioning

confidence: 99%

“…Unlike in other tissue microenvironments where CD11c (gene name Itgax ) is used to specifically identify dendritic cells, most non-neutrophil myeloid cells, including macrophages and some monocytes, express CD11c + ( Kawakami et al, 2013 ; Lever et al, 2019 ; Salei et al, 2020 ; Zimmerman et al, 2020 ; Salei et al, 2021 ; Privratsky et al, 2023 ). The roles of CD11c-expressing myeloid cells during AKI are complex and context-specific as CD11c + myeloid cells promote cyst formation in a cystic disease model ( Zimmerman et al, 2019 ); whereas deletion of CD11c + cells aggravates cisplatin- and sepsis-induced AKI ( Tadagavadi and Reeves, 2010 ; Privratsky et al, 2023 ), and impairs the healing process and promotes pro-inflammatory cytokine generation following ischemic AKI ( Kim et al, 2010 ; Lu et al, 2012 ). Indeed, depending on their activation and subsequent polarization phenotype, CD11c-expressing myeloid cells can secrete both pro- and anti-inflammatory cytokines to modulate the response to kidney injury.…”

Section: Introductionmentioning

confidence: 99%

Novel anti-inflammatory effects of the IL-1 receptor in kidney myeloid cells following ischemic AKI

Chen,

Lu,

Whitney

et al. 2024

Front. Mol. Biosci.

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Introduction: Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1β (IL-1β) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI.Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre+/IL-1R1fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre-/IL-1R1fl/fl–Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice.Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1β) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1β-induced tubular cell injury.Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.

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“…Our scRNA-seq cell isolation protocol has been previously described. 16 Kidney digest was performed with liberase TM (0.3 mg/ml, Roche, Basel, Switzerland, 291963), hyaluronidase (10 mg/ml, Sigma, H4272), and DNaseI (20 mg/ml) at 37°C for 20 minutes. After centrifugation, cell pellets were incubated with ammonium-chloride-potassium lysing buffer (ThermoFisher A1049201) and again centrifuged.…”

Section: Methodsmentioning

confidence: 99%

Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI

Ren,

Liu,

et al. 2023

JASN

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Background: Activation of the type 1 interleukin 1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of acute kidney injury (AKI). IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. Methods: To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid (AA) exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. Results: Single-cell RNA sequencing analyses demonstrated robust IL-1 expression in myeloid cell populations and low level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death via local suppression of apolipoprotein M (Apom). In contrast, IL-1R1 activation in endothelial cells ameliorated AA-induced AKI by restoring VEGFA-dependent endothelial cell viability and density. Conclusions: These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI following toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.

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A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury

Cited by 21 publications

References 54 publications

Astragaloside IV modulates gut macrophages M1/M2 polarization by reshaping gut microbiota and SCFA in sepsis

Astragaloside IV modulates gut macrophages M1/M2 polarization by reshaping gut microbiota and SCFA in sepsis

Novel anti-inflammatory effects of the IL-1 receptor in kidney myeloid cells following ischemic AKI

Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI

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