Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis

Richoz, Nathan; Tuong, Zewen Kelvin; Loudon, Kevin; Patiño-Martínez, Eduardo; Ferdinand, John R.; Portet, Anaïs; Bashant, Kathleen R.; Thevenon, Emeline; Rucci, Francesca; Hoyler, Thomas; Junt, Tobias; Kaplan, Mariana J.; Siegel, Richard M.; Clatworthy, Menna R.

doi:10.1172/jci.insight.159751

Cited by 12 publications

(5 citation statements)

References 66 publications

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“…These results suggest that myeloid cells including monocytes and macrophages M2 are the main infiltrating immune cells in the glomerulus of LN affected kidneys. These cells may significantly contribute to LN disease pathogenesis ( 22 , 40 , 41 ).…”

Section: Resultsmentioning

confidence: 99%

“…In LN, immune cell infiltration, particularly monocytes and macrophages, plays a crucial role in disease progression by accumulating in the kidney and promoting inflammation through the production of chemokines and cytokines ( 40 , 41 , 91 – 94 ). Additionally, LN patients’ pDCs produce type I interferons, which can activate B cells and lead to the production of autoreactive antibodies ( 95 – 97 ).…”

Section: Discussionmentioning

confidence: 99%

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Identification of driver genes in lupus nephritis based on comprehensive bioinformatics and machine learning

Wang,

Hu,

Pei

et al. 2023

Front. Immunol.

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BackgroundLupus nephritis (LN) is a common and severe glomerulonephritis that often occurs as an organ manifestation of systemic lupus erythematosus (SLE). However, the complex pathological mechanisms associated with LN have hindered the progress of targeted therapies.MethodsWe analyzed glomerular tissues from 133 patients with LN and 51 normal controls using data obtained from the GEO database. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis. Weighted gene co-expression network analysis (WGCNA) was utilized to identify key gene modules. The least absolute shrinkage and selection operator (LASSO) and random forest were used to identify hub genes. We also analyzed immune cell infiltration using CIBERSORT. Additionally, we investigated the relationships between hub genes and clinicopathological features, as well as examined the distribution and expression of hub genes in the kidney.ResultsA total of 270 DEGs were identified in LN. Using weighted gene co-expression network analysis (WGCNA), we clustered these DEGs into 14 modules. Among them, the turquoise module displayed a significant correlation with LN (cor=0.88, p<0.0001). Machine learning techniques identified four hub genes, namely CD53 (AUC=0.995), TGFBI (AUC=0.997), MS4A6A (AUC=0.994), and HERC6 (AUC=0.999), which are involved in inflammation response and immune activation. CIBERSORT analysis suggested that these hub genes may contribute to immune cell infiltration. Furthermore, these hub genes exhibited strong correlations with the classification, renal function, and proteinuria of LN. Interestingly, the highest hub gene expression score was observed in macrophages.ConclusionCD53, TGFBI, MS4A6A, and HERC6 have emerged as promising candidate driver genes for LN. These hub genes hold the potential to offer valuable insights into the molecular diagnosis and treatment of LN.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of driver genes in lupus nephritis based on comprehensive bioinformatics and machine learning

Wang,

Hu,

Pei

et al. 2023

Front. Immunol.

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“…They enter tissues after inflammatory cues are released or changes in homeostasis occur (Robinson et al, 2021). Monocytes exhibit high plasticity and may differentiate into various monocyte-derived cells in tissues for replacing resident tissue macrophages, enhancing inflammation, or promoting inflammatory responses (Richoz et al, 2022). They strongly influence tissue homeostasis and pathogenic or productive immunity (Guilliams et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Coniferyl ferulate alleviate xylene-caused hematopoietic stem and progenitor cell toxicity by Mgst2

Yin,

Ou,

Zhu

et al. 2024

Front. Pharmacol.

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Xylene exposure is known to induce toxicity in hematopoietic stem and progenitor cells (HSPCs), leading to bone marrow suppression and potential leukemogenesis. However, research on the gene expression profiles associated with xylene-induced toxicity in HSPCs, and effective therapeutic interventions, remains scarce. In our study, we employed single-cell RNA sequencing to capture the transcriptomic shifts within bone marrow HSPCs both prior to and following treatment with coniferyl ferulate (CF) in a mouse model of xylene-induced hematotoxicity. Subsequently, we pinpointed CF as a targeted agent using SPR-LC/MS analysis. This enabled us to confirm the link between the gene Mgst2 and specific cellular subtypes. Our data revealed that CF significantly countered the reduction of both monocyte and neutrophil progenitor cells, which are commonly affected by xylene toxicity. Through targeted analysis, we identified Mgst2 as a direct molecular target of CF. Notably, Mgst2 is preferentially expressed in neutrophil progenitor cells and is implicated in mitochondrial metabolic processes. By selectively inhibiting Mgst2 in bone marrow, we observed amelioration of xylene-induced hematotoxic effects. In summary, our findings suggest that coniferyl ferulate can mitigate the detrimental impact of xylene on hematopoietic stem and progenitor cells by targeting Mgst2, particularly within subpopulations of neutrophil progenitors. This discovery not only advances our comprehension of the cellular response of HSPCs to xenobiotic stressors like xylene but also identifies CF and Mgst2 as potential therapeutic targets for alleviating xylene-induced hematotoxicity.

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“…It is well known that macrophages play an important role in the pathogenesis of LN [28][29][30], but less is known about macrophage subtypes in the pathogenesis of LN, especially in human LN. In a previous study, we showed that surprisingly, most macrophages in the kidneys of adult lupus patients expressed CD163 and were classified as predominantly M2-like macrophages [25].…”

Section: Macrophage Subpopulations In Pediatric and Adult Patients Wi...mentioning

confidence: 99%

Macrophage subpopulations in pediatric patients with lupus nephritis and other inflammatory diseases affecting the kidney

Sandersfeld,

Büttner-Herold,

Ferrazzi

et al. 2024

Arthritis Res Ther

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Background Macrophages play an important role in the pathogenesis of lupus nephritis (LN), but less is known about macrophage subtypes in pediatric LN. Here we compared renal inflammation in LN with other inflammatory pediatric kidney diseases and assessed whether inflammation correlates with clinical parameters. Methods Using immunofluorescence microscopy, we analyzed renal biopsies from 20 pediatric patients with lupus nephritis (ISN/RPS classes II–V) and pediatric controls with other inflammatory kidney diseases for infiltration with M1-like (CD68 + /CD206 − , CD68 + /CD163 −), M2a-like (CD206 + /CD68 +), and M2c-like macrophages (CD163 + /CD68 +) as well as CD3 + T-cells, CD20 + B-cells, and MPO + neutrophilic granulocytes. In addition, the correlation of macrophage infiltration with clinical parameters at the time of renal biopsy, e.g., eGFR and serum urea, was investigated. Macrophage subpopulations were compared with data from a former study of adult LN patients. Results The frequency of different macrophage subtypes in biopsies of pediatric LN was dependent on ISN/RPS class and showed the most pronounced M1-like macrophage infiltration in patients with LN class IV, whereas M2c-like macrophages were most abundant in class III and IV. Interestingly, on average, only half as many macrophages were found in renal biopsies of pediatric LN compared to adult patients with LN. The distribution of frequencies of macrophage subpopulations, however, was different for CD68 + CD206 + (M2a-like) but comparable for CD68 + CD163 − (M1-like) CD68 + CD163 + (M2c-like) cells in pediatric and adult patients. Compared to other inflammatory kidney diseases in children, fewer macrophages and other inflammatory cells were found in kidney biopsies of LN. Depending on the disease, the frequency of individual immune cell types varied, but we were unable to confirm disease-specific inflammatory signatures in our study due to the small number of pediatric cases. Worsened renal function, measured as elevated serum urea and decreased eGFR, correlated particularly strongly with the number of CD68 + /CD163 − M1-like macrophages and CD20 + B cells in pediatric inflammatory kidney disease. Conclusion Although M1-like macrophages play a greater role in pediatric LN patients than in adult LN patients, M2-like macrophages appear to be key players and are more abundant in other pediatric inflammatory kidney diseases compared to LN.

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Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis

Cited by 12 publications

References 66 publications

Identification of driver genes in lupus nephritis based on comprehensive bioinformatics and machine learning

Identification of driver genes in lupus nephritis based on comprehensive bioinformatics and machine learning

Coniferyl ferulate alleviate xylene-caused hematopoietic stem and progenitor cell toxicity by Mgst2

Macrophage subpopulations in pediatric patients with lupus nephritis and other inflammatory diseases affecting the kidney

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