TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis

Yang, Jun; Yin, Shasha; Bi, Fangfang; Liu, Lin; Qin, Tian; Wang, Hongwei; Cao, Wangsen

doi:10.1007/s00109-016-1479-z

Cited by 28 publications

(19 citation statements)

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“…HDAC3 elevation in adenine mouse kidney is likely due to the renal damageassociated hyperactive transforming growth factor-b (TGFb) activity because adenine does not increase HDAC3 in cultured renal cells (data not shown), whereas crystallized adenine in kidney blocks renal tubules and causes severe renal injuries, which are accompanied by increased TGFb. 33,52 In addition, recent studies indicated that TGFb preferentially increased HDAC3 expression in renal cells and macrophages, 53,54 suggesting that deregulated HDAC3 expression might be a general and key event mediating the pathological changes of CKD. HDAC3 inhibition has been shown to positively affect PPARg activities in adipocytes and adipose tissues.…”

Section: Discussionmentioning

confidence: 99%

Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease

Lin

Qin

et al. 2017

Kidney International

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Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation-Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A. This inhibition up-regulated Klotho mainly through an enhancement of PPARγ acetylation, stimulation of PPARγ binding to Klotho promoter, and PPARγ-dependent increase in Klotho transcription, with a substantial control of the regulation occurring via PPARγ acetylations on K240 and K265. Consistently trichostatin A-induced reversal of Klotho loss and renoprotective effects were abrogated in PPARγ knockout mice, supporting that PPARγ is an essential acetylation target for Klotho restoration and renal protection. Intriguingly, the kidneys of adenine-fed CKD mice displayed deregulated HDAC3 up-regulation. Selective HDAC3 inhibition effectively alleviated Klotho loss and kidney injury, whereas the protective effects were largely abolished when Klotho was knocked down by siRNA, suggesting that aberrant HDAC3 and Klotho loss are crucial components involved in the renal damage of mice with CKD. Our study identified an important signaling cascade and key components contributing to the pathogenesis of CKD. Thus, targeting Klotho loss by HDAC3 inhibition has promising therapeutic potential for the reduction of CKD progression.

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Section: Discussionmentioning

confidence: 99%

Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease

Lin

Qin

et al. 2017

Kidney International

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“…Among them, macrophages—which possess the functions of phagocytosis and antigen presentation—have two major characteristics, i.e., diversity and plasticity. 4 , 6 , 25 As the front line of defense cells, macrophages can activate the immune system to trigger an immune response. The results of immunofluorescence verified that the recruitment of macrophages was upregulated in the corneal stroma of mouse corneas after infection with A. fumigatus .…”

Section: Discussionmentioning

confidence: 99%

“…During these inflammatory responses, macrophages act as an immunomodulatory agent and play a major role in the phagocytosis of fungal spores and hyphae, as well as antigen cross-presentation. 4 In addition, macrophages can modulate their phenotype to respond to the local microenvironment. Two functionally distinct subsets of macrophages have been recognized: proinflammatory (M1) and anti-inflammatory (M2) macrophages.…”

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confidence: 99%

Indoleamine 2,3-Dioxygenase Regulates Macrophage Recruitment, Polarization and Phagocytosis in Aspergillus Fumigatus Keratitis

Jiang

Zhang

Zhao

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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To explore the influence of indoleamine 2,3-dioxygenase (IDO) on macrophage recruitment, polarization and phagocytosis in Aspergillus fumigatus keratitis. METHODS. A murine model of A. fumigatus keratitis and peritoneal macrophages incubated with the hyphae of A. fumigatus were used. Macrophage recruitment in corneas was evaluated using immunofluorescence staining. The polarization of macrophages, which was stimulated by A. fumigatus and pretreatment with or without 1-methyltryptophan (1-MT), interferon gamma (IFNG), extracellular regulated protein kinases (ERK) antagonist, and p38 antagonist, was determined using reverse-transcription polymerase chain reaction and flow cytometry. P38 and ERK levels were determined using Western blotting. Macrophage phagocytosis was examined using colony-forming units. RESULTS. Compared with the A.F. group, recruitment of macrophages increased, tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression decreased, whereas arginase-1 (Arg-1) and interleukin-10 (IL-10) expression increased in the mouse corneas of the 1-MT+A.F. group. The ratio of CD206 + /CD86 + macrophages in the corneas and spleens of 1-MT+A.F. group increased. Furthermore, in peritoneal macrophages stimulated by A. fumigatus, 1-MT promoted Arg-1 and IL-10 expression while upregulating the ratio of CD206 + /CD86 + macrophages. Conversely, IDO agonist IFNG promoted TNF-α and iNOS expression, inhibited Arg-1 and IL-10 expression and downregulated the ratio of CD206 + /CD86 + macrophages. The role of IFNG was reversed by the antagonist of P38 or ERK. P38 and ERK levels were downregulated in corneas of 1-MT+A.F. group. Besides, IFNG inhibited macrophage phagocytosis. CONCLUSIONS. IDO inhibited macrophage recruitment and phagocytosis in A. fumigatus keratitis. Mechanistically, IDO is involved in M1 macrophage polarization in A. fumigatus keratitis through a MAPK/ERK-dependent pathway.

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“…TNF-α is a common inhibitor of M2 TAMs, which can inhibit the differentiation of macrophages to M2 by direct or indirect production of IL-13, thereby reducing the number of M2 TAMs 48,49 . TGFβ promotes the differentiation of nonactivated macrophages into M2 TAMs by upregulating the expression of IL-10 and downregulating the expression of TNF-α and IL-12 50,51 . The expression of TNF-α and TGF-β in coculture supernatants of macrophages and NPC cells was detected by ELISA.…”

Section: Discussionmentioning

confidence: 99%

EB virus-induced ATR activation accelerates nasopharyngeal carcinoma growth via M2-type macrophages polarization

et al. 2020

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Chronic inflammation induced by persistent viruses infection plays an essential role in tumor progression, which influenced on the interaction between the tumor cells and the tumor microenvironment. Our earlier study showed that ATR, a key kinase participant in single-stranded DNA damage response (DDR), was obviously activated by Epstein–Barr virus (EBV) in nasopharyngeal carcinoma (NPC). However, how EBV-induced ATR activation promotes NPC by influencing inflammatory microenvironment, such as tumor-associated macrophages (TAMs), remains elusive. In this study, we showed that EBV could promote the expression of p-ATR and M2-type TAMs transformation in clinical NPC specimens. The expression of p-ATR and M2-type TAMs were closely correlated each other and involved in TNM stage, lymph node metastasis and poor prognosis of the patients. In addition, the expression levels of CD68+CD206+, Arg1, VEGF, and CCL22 were increased in EB+ CNE1 cells, and decreased when ATR was inhibited. In the nude mice, EBV-induced ATR activation promoted subcutaneous transplanted tumor growth, higher expression of Ki67 and lung metastasis via M2-type TAMs recruitment. Experimental data also showed that the polarization of M2, the declined tumor necrosis factor-α (TNF-α) and increased transforming growth factor-β (TGF-β) were associated with ATR. Meanwhile, ATR activation could promote PPAR-δ and inhibited c-Jun and p-JNK expression, then downregulate JNK pathway. Collectively, our current study demonstrated the EBV infection could activate the ATR pathway to accelerate the transition of TAMs to M2, suggesting ATR knockdown could be a potential effective treatment strategy for EBV-positive NPC.

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TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis

Cited by 28 publications

References 50 publications

Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease

Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease

Indoleamine 2,3-Dioxygenase Regulates Macrophage Recruitment, Polarization and Phagocytosis in Aspergillus Fumigatus Keratitis

EB virus-induced ATR activation accelerates nasopharyngeal carcinoma growth via M2-type macrophages polarization

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