New inducible mast cell-deficient mouse model (Mcpt5/Cma1)

Sasaki, Hayato; Imanishi, Madoka; Fujikura, Daisuke; Sugiyama, Makoto; Tanimoto, Kyosuke; Mochiji, Yohei; Takahashi, Yuki; Hiura, Koki; Watanabe, Masaki; Kashimoto, Takeshi; Nakano, Kenta; Okamura, Tadashi; Sasaki, Nobuya

doi:10.1016/j.bbrc.2021.03.025

Cited by 11 publications

(8 citation statements)

References 40 publications

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“…These mediators can cause allergic reactions, inflammation and pain. 28 The MCPT5 expression in mast cells is governed by several factors, including growth factors, cytokines, and allergens. MCPT5 expression in mast cells is mainly induced by cytokines such as IL-3, TGF-β, and SCF.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Stem Cell Factor by Forskolin Inhibits the Progression of Tubule Interstitial Fibrosis

Vadnal,

Babu,

Manikantha

et al. 2024

Journal of Pharmacology and Pharmacotherapeutics

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Purpose: Forskolin is primarily found in the roots of the Coleus forskohlii plant, historically employed in Southeast Asian and Indian Ayurvedic medicine. Mast cells play a crucial role in fibrosis progression, yet their activation and inhibition in animal models are understudied; thus, we explored forskolin’s impact on kidney fibrosis. Materials and Methods: Forskolin was evaluated in a mouse model for stem cell factor-induced histamine release, and plasma histamine levels were measured using the enzyme-linked immunosorbent assay. Kidney fibrosis was developed by unilateral ureteral obstruction (UUO). Renal function was assessed by spectrophotometric measurements of serum blood urea nitrogen (BUN) and creatinine. The gene expression of collagen, transforming growth factor-beta (TGF-β), α-smooth muscle actin (α-SMA), interleukin-1 beta (IL-1β), and mast cell protease-5 (MCPT-5) in the kidney was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Histopathological changes in the renal tissues were examined by hematoxylin and eosin (H&E) and Masson’s trichome stain. Results: Our results showed that 3 mg/kg forskolin inhibited SCF-induced plasma histamine release in a mouse model. In the 7-day UUO model, forskolin significantly showed inhibition of serum creatinine and blood urea nitrogen compared with the disease group. Forskolin significantly inhibited elevated expression of collagen, TGF-β, α-SMA, IL-1β, and MCPT-5 in the kidneys. Histopathological observation of H&E and Masson trichome-stained kidney forskolin demonstrated a reduction in inflammatory cells, pelvic and tubular dilation, and fibrosis. Conclusion: Forskolin showed an anti-fibrotic effect in UUO-induced renal fibrotic mice. Most significantly, forskolin administration showed a decrease in the expression of the mast cell protease MCPT5 in the kidneys. These results imply that forskolin, through modifying SCF activity, may be a viable potential treatment for the attenuation of tubule-interstitial fibrosis.

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Section: Discussionmentioning

confidence: 99%

Modulation of Stem Cell Factor by Forskolin Inhibits the Progression of Tubule Interstitial Fibrosis

Vadnal,

Babu,

Manikantha

et al. 2024

Journal of Pharmacology and Pharmacotherapeutics

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“…Although mast cells may play pivotal roles in the development of colitis-associated cancer, only the data of mRNA expressions were shown in this study. To prove the roles of mast cells in colitis-associated cancers, further experiments are needed, for example, an experiment to see the role of mast cells during colitis with or without infliximab treatment using a mast cell-deficient mouse model [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation

Wang

Ohnuma

Suzuki

et al. 2023

CIMB

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Inflammatory bowel diseases (IBDs), such as Crohn’s disease or ulcerative colitis, can be treated with anti TNF-alpha (TNF-α) antibodies (Abs), but they also put patients with IBDs at risk of cancer. We aimed to determine whether the anti TNF-α Ab induces colon cancer development in vitro and in vivo, and to identify the genes involved in colitis-associated cancer. We found that TNF-α (50 ng/mL) inhibited the proliferation, migration, and invasion of HCT8 and COLO205 colon cancer cell lines and that anti TNF-α Ab neutralized TNF-α inhibition in vitro. The effects of anti TNF-α Ab, infliximab (10 mg/kg) were investigated in mouse models of colitis-associated cancer induced by intraperitoneally injected azoxymethane (AOM: 10 mg/kg)/orally administered dextran sodium sulfate (DSS: 2.5%) (AOM/DSS) in vivo. Infliximab significantly attenuated the development of colon cancer in these mice. Microarray analyses and RT-qPCR revealed that mast cell protease 1, mast cell protease 2, and chymase 1 were up-regulated in cancer tissue of AOM/DSS mice; however, those mast cell related genes were downregulated in cancer tissue of AOM/DSS mice with infliximab. These results suggested that mast cells play a pivotal role in the development of cancer associated with colitis in AOM/DSS mice.

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“…Based on our finding of differential expression of MCPT1 and MCPT4 in peri vs. intravascular mast cells, this should be possible using a genetic approach that utilizes Mcpt1- target or Mcpt4 -target gene expression akin to Mcpt1-Cre-iDTR mice ( 53 ). Our future research will focus on generating MC-subpopulation-specific mast cell strains, such as the Mcpt1 DTR murine model, which would enable selective in vivo depletion of Mcpt1-expressing mast cells ( 54 ). Alternatively, it might be possible to generate a depletion model with CRISPR to selectively remove the identified mast cell subpopulations in vitro in the presence of mast cell stabilizer.…”

Section: Discussionmentioning

confidence: 99%

Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice

Peng,

Kenney,

de Mesy Bentley

et al. 2023

Front. Immunol.

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ObjectiveInflammatory-erosive arthritis is exacerbated by dysfunction of joint-draining popliteal lymphatic vessels (PLVs). Synovial mast cells are known to be pro-inflammatory in rheumatoid arthritis (RA). In other settings they have anti-inflammatory and tissue reparative effects. Herein, we elucidate the role of mast cells on PLV function and inflammatory-erosive arthritis in tumor necrosis factor transgenic (TNF-tg) mice that exhibit defects in PLVs commensurate with disease progression.MethodsWhole mount immunofluorescent microscopy, toluidine blue stained histology, scanning electron microscopy, and in silico bioinformatics were performed to phenotype and quantify PLV mast cells. Ankle bone volumes were assessed by μCT, while corresponding histology quantified synovitis and osteoclasts. Near-infrared indocyanine green imaging measured lymphatic clearance as an outcome of PLV draining function. Effects of genetic MC depletion were assessed via comparison of 4.5-month-old WT, TNF-tg, MC deficient KitW-sh/W-sh (cKit-/-), and TNF-tg x cKit-/- mice. Pharmacological inhibition of mast cells was assessed by treating TNF-tg mice with placebo or cromolyn sodium (3.15mg/kg/day) for 3-weeks.ResultsPLVs are surrounded by MCT+/MCPT1+/MCPT4+ mast cells whose numbers are increased 2.8-fold in TNF-tg mice. The percentage of peri-vascular degranulating mast cells was inversely correlated with ICG clearance. A population of MCT+/MCPT1-/MCPT4- mast cells were embedded within the PLV structure. In silico single-cell RNA-seq (scRNAseq) analyses identified a population of PLV-associated mast cells (marker genes: Mcpt4, Cma1, Cpa3, Tpsb2, Kit, Fcer1a & Gata2) with enhanced TGFβ-related signaling that are phenotypically distinct from known MC subsets in the Mouse Cell Atlas. cKit-/- mice have greater lymphatic defects than TNF-tg mice with exacerbation of lymphatic dysfunction and inflammatory-erosive arthritis in TNF-tg x cKit-/- vs. TNF-Tg mice. Cromolyn sodium therapy stabilized PLV mast cells, increased TNF-induced bone loss, synovitis, and osteoclasts, and decreased ICG clearance.ConclusionsMast cells are required for normal lymphatic function. Genetic ablation and pharmacological inhibition of mast cells exacerbates TNF-induced inflammatory-erosive arthritis with decreased lymphatic clearance. Together, these findings support an inflammatory role of activated/degranulated peri-PLV mast cells during arthritic progression, and a homeostatic role of intra-PLV mast cells, in which loss of the latter dominantly exacerbates arthritis secondary to defects in joint-draining lymphatics, warranting investigation into specific cellular mechanisms.

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New inducible mast cell-deficient mouse model (Mcpt5/Cma1)

Cited by 11 publications

References 40 publications

Modulation of Stem Cell Factor by Forskolin Inhibits the Progression of Tubule Interstitial Fibrosis

Modulation of Stem Cell Factor by Forskolin Inhibits the Progression of Tubule Interstitial Fibrosis

Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation

Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice

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