The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring

Tang, Patrick Ming‐Kuen; Zhou, Shuang; Li, Chunjie; Liao, Jinyue; Xiao, Jun; Wang, Qing-Ming; Lian, Guang-Yu; Li, Jinhong; Huang, Xiao‐Ru; To, Ka–Fai; Ng, Chi‐Fai; Chong, Charing Ching‐Ning; Ma, Rong; Lee, Tin‐Lap; Lan, Hui‐Yao

doi:10.1016/j.kint.2017.07.026

Cited by 94 publications

(130 citation statements)

References 51 publications

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“…Some lineage-tracing studies have determined endogenous stromal cells (fibroblasts and pericytes) as the primary source [36,37], and tubular epithelium undergoing EMT as a plausible source in advanced stages where the basement membrane have suffered severe damage [38]. Nonetheless, subsequent studies have determined that Mϕ are the main participants as revealed by the macrophage-to-myofibroblast transition occurring in active renal fibrosis [39,40], with the M2 phenotype being the predominant cell type [41]. Nevertheless, when Mϕ becomes anti-inflammatory they support the resolution of inflammation.…”

Section: Macrophage Phenotype and Fibrosismentioning

confidence: 99%

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

Calle

Hotter

2020

IJMS

121

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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN.

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Section: Macrophage Phenotype and Fibrosismentioning

confidence: 99%

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

Calle

Hotter

2020

IJMS

121

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“…For primary culture of BMDM, bone marrow cells were harvested from 8-to 10-week-old C57BL/6J mice as previously done (23)(24)(25). In brief, bone marrow cells were harvested from femur and tibia via fine dissection.…”

Section: Primary Culture Of Bmdmmentioning

confidence: 99%

“…The chromatin immunoprecipitation (ChIP) assay was performed with the SimpleChIP Enzymatic Chromatin IP Kit (Cell Signaling Technology, #9003S) as previously described (24). In brief, immunoprecipitation was performed with the antibody against NF-kB subunit p65 (Cell Signaling Technology, #6956) or a normal IgG as the negative control.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

“…To identify the mechanism of Mincle in TAM-mediated cancer promotion, we elucidated the 10X scRNA-seq data of NSCLC in Fig. 1A with unbiased network and enrichment analysis (24). By using the DEG of Mincle þ TAM in NSCLC, a regulatory gene network enriched with NF-kB signaling pathway was reconstructed by Meta-Core bioinformatic platform ( Fig.…”

Section: Mincle Enhanced the Protumoral Activity Of Tam Via The Syk/nmentioning

confidence: 99%

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The Mincle/Syk/NF-κB Signaling Circuit Is Essential for Maintaining the Protumoral Activities of Tumor-Associated Macrophages

Xue

Wang

et al. 2020

Cancer Immunology Research

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Tumor-associated macrophages (TAM) have important roles in cancer progression, but the signaling behind the formation of protumoral TAM remains understudied. Here, by single-cell RNA sequencing, we revealed that the pattern recognition receptor Mincle was highly expressed in TAM and significantly associated with mortality in patients with non-small cell lung cancer. Cancer cells markedly induced Mincle expression in bone marrow-derived macrophages (BMDM), thus promoting cancer progression in invasive lung carcinoma LLC and melanoma B16F10 in vivo and in vitro. Mincle was predominately expressed in the M2-like TAM in non-small cell lung carcinoma and LLC tumors, and silencing of Mincle unexpectedly promoted M1-like phenotypes in vitro. Mechanistically, we discovered a novel Mincle/Syk/NF-kB signaling pathway in TAM needed for executing their TLR4independent protumoral activities. Adoptive transfer of Minclesilenced BMDM significantly suppressed TAM-driven cancer progression in the LLC-bearing NOD/SCID mice. By modifying our well-established ultrasound microbubble-mediated gene transfer protocol, we demonstrated that tumor-specific silencing of Mincle effectively blocked Mincle/Syk/NF-kB signaling, therefore inhibiting the TAM-driven cancer progression in the syngeneic mouse cancer models. Thus, our findings highlight the function of Mincle as a novel immunotherapeutic target for cancer via blocking the Mincle/Syk/NF-kB circuit in TAM.

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“…Protein from renal cortex and cultured cells was extracted using the radioimmunoprecipitation assay lysis buffer. Western blot analysis was performed as described previously (25). In brief, after blocking nonspecific binding with 5% BSA, nitrocellulose membranes were then incubated overnight at 4°C with primary antibodies against phospho-Smad3 (Cell Signaling Technology, Danvers, MA) and Smad3 (Santa Cruz Biotechnology, Santa Cruz, CA), collagens I and collagen IV (Southern Biotechnology Associates, Birmingham, AL), and b-actin (Santa Cruz Biotechnology), followed by IRDye800-conjugated secondary antibodies (Rockland Immunochemicals, Gilbertsville, PA).…”

Section: Western Blot Analysismentioning

confidence: 99%

Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b

et al. 2017

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Transforming growth factor-β/Smad signaling plays an important role in diabetic nephropathy. The current study identified a novel Smad3-dependent long noncoding RNA (lncRNA) Erbb4-IR in the development of type 2 diabetic nephropathy (T2DN) in mice. We found that Erbb4-IR was highly expressed in T2DN of mice and specifically induced by advanced glycosylation end products (AGEs) via a Smad3-dependent mechanism. The functional role of Erbb4-IR in T2DN was revealed by kidney-specific silencing of Erbb4-IR to protect against the development of T2DN, such as elevated microalbuminuria, serum creatinine, and progressive renal fibrosis in mice, and to block AGE-induced collagen I and IV expression in mouse mesangial cells (mMCs) and mouse tubular epithelial cells (mTECs). Mechanistically, we identified that the Erbb4-IR-microRNA (miR)-29b axis was a key mechanism of T2DN because Erbb4-IR was able to bind the 3' untranslated region of miR-29b genomic sequence to suppress miR-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR increased miR-29b and therefore protected the kidney from progressive renal injury in mice and prevented mTECs and mMCs from AGE-induced loss of miR-29b and fibrotic response in vitro. Collectively, we identify that Erbb4-IR is a Smad3-dependent lncRNA that promotes renal fibrosis in T2DN by suppressing miR-29b. Targeting Erbb4-IR may represent a novel therapy for T2DN.

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The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring

Cited by 94 publications

References 51 publications

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

The Mincle/Syk/NF-κB Signaling Circuit Is Essential for Maintaining the Protumoral Activities of Tumor-Associated Macrophages

Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b

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