Tissue-Resident Macrophages Promote Renal Cystic Disease

Zimmerman, Kurt A.; Song, Chun-Yan; Li, Zhang; Lever, Jeremie M.; Crossman, David K.; Rains, Addison; Aloria, Ernald J; Gonzalez, Nancy M.; Bassler, John; Zhou, Juling; Crowley, Michael R.; Revell, Dustin Z.; Yan, Zhaoqi; Shan, Dan; Benveniste, Etty N.; George, James F.; Mrug, Michal; Yoder, Bradley K.

doi:10.1681/asn.2018080810

Cited by 62 publications

(88 citation statements)

References 46 publications

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“…However, the importance of infiltrating macrophages may be model specific because genetic deletion of CCR2, the Ccl2 ligand, did not affect cyst severity in the cpk mouse model (23). Of interest, our recent data also indicate that inhibition of resident macrophage proliferation and accumulation results in a significant reduction in cyst severity (11). Regardless of the source of macrophages, these cells are able to release inflammatory cytokines that promote cyst growth.…”

Section: Introductionmentioning

confidence: 89%

“…A possible mechanism explaining the variability in phenotypic progression is the presence of "modifying factors" that can accelerate cyst growth in the presence of PKD mutations (3)(4)(5)(6). Renal injury is one example of a modifier that can accelerate cystogenesis (3,(6)(7)(8)(9)(10)(11). We have shown that unilateral nephrectomy (UNx) in adult conditional Pkd1 knockout mice leads to accelerated cyst growth (6,9).…”

Section: Introductionmentioning

confidence: 99%

“…Among a number of factors that are involved in the pathogenesis of PKD, recent evidence suggests that innate immunity, particularly macrophages, plays a significant role in cyst development (11,(15)(16)(17)(18)(19)(20)(21). These studies demonstrated that there are an increased number of macrophages in cystic kidneys and that these macrophages drive proinflammatory cytokinemediated tubular cell injury, proliferation, and cyst formation (15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

et al. 2020

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Background Autosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2. Macrophages and their associated inflammatory cytokines promote cyst progression; however, transcription factors within macrophages that control cytokine production and cystic disease are unknown.Methods In these studies, we used conditional Pkd1 mice to test the hypothesis that macrophage-localized interferon regulatory factor-5 (IRF5), a transcription factor associated with production of cyst-promoting cytokines (TNFa, IL-6), is required for accelerated cyst progression in a unilateral nephrectomy (1K) model. Analyses of quantitative real-time PCR (qRT-PCR) and flow-cytometry data 3 weeks post nephrectomy, a time point before the onset of severe cystogenesis, indicate an accumulation of inflammatory infiltrating and resident macrophages in 1K Pkd1 mice compared with controls. qRT-PCR data from FACS cells at this time demonstrate that macrophages from 1K Pkd1 mice have increased expression of Irf5 compared with controls. To determine the importance of macrophage-localized Irf5 in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K Pkd1 mice and analyzed the effect on macrophage numbers, cytokine production, and renal cystogenesis 6 weeks post nephrectomy.Results Analyses of qRT-PCR and IRF5 ASO treatment significantly reduced macrophage numbers, Irf5 expression in resident-but not infiltrating-macrophages, and the severity of cystic disease. In addition, IRF5 ASO treatment in 1K Pkd1 mice reduced Il6 expression in resident macrophages, which was correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression.Conclusions These data suggest that Irf5 promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

et al. 2020

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“…While multiple intrinsic defects in tubular cells homeostasis are observed in ADPKD [34][35][36] , accumulating evidence demonstrates that interstitial inflammation also plays an important role in the disease [6][7][8]10,37,38 . Yet, the nature of the factors mediating communication between tubular and immune cells and their impact on disease expression are not well-characterized.…”

Section: Discussionmentioning

confidence: 99%

“…First, polycystin deficiency triggers monocyte migration to the kidney through the induction of CCL2 7,10 . Second, kidney injury has been shown to promote cyst progression by triggering CSF1 dependent resident macrophage proliferation 37 . In turn, infiltrating macrophages drive tubular cell proliferation, possibly by releasing arginine metabolites 8 .…”

Section: Discussionmentioning

confidence: 99%

Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

Viau

Baziz

Aka

et al. 2019

Preprint

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words)The inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes STAT3 activation. Surprisingly, while disrupting Stat3 in Pkd1 deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

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A Pathologically Friendly Strategy for Determining the Organ‐specific Spatial Tumor Microenvironment Topology in Lung Adenocarcinoma Through the Integration of snRandom‐seq and Imaging Mass Cytometry

Sun,

Teng,

Liu

et al. 2024

Advanced Science

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Heterogeneous organ‐specific responses to immunotherapy exist in lung cancer. Dissecting tumor microenvironment (TME) can provide new insights into the mechanisms of divergent responses, the process of which remains poor, partly due to the challenges associated with single‐cell profiling using formalin‐fixed paraffin‐embedded (FFPE) materials. In this study, single‐cell nuclei RNA sequencing and imaging mass cytometry (IMC) are used to dissect organ‐specific cellular and spatial TME based on FFPE samples from paired primary lung adenocarcinoma (LUAD) and metastases. Single‐cell analyses of 84 294 cells from sequencing and 250 600 cells from IMC reveal divergent organ‐specific immune niches. For sites of LUAD responding well to immunotherapy, including primary LUAD and adrenal gland metastases, a significant enrichment of B, plasma, and T cells is detected. Spatially resolved maps reveal cellular neighborhoods recapitulating functional units of the tumor ecosystem and the spatial proximity of B and CD4+ T cells at immunogenic sites. Various organ‐specific densities of tertiary lymphoid structures are observed. Immunosuppressive sites, including brain and liver metastases, are deposited with collagen I, and T cells at these sites highly express TIM‐3. This study originally deciphers the single‐cell landscape of the organ‐specific TME at both cellular and spatial levels for LUAD, indicating the necessity for organ‐specific treatment approaches.

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Tissue-Resident Macrophages Promote Renal Cystic Disease

Cited by 62 publications

References 46 publications

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

A Pathologically Friendly Strategy for Determining the Organ‐specific Spatial Tumor Microenvironment Topology in Lung Adenocarcinoma Through the Integration of snRandom‐seq and Imaging Mass Cytometry

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