The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3+IL-17+ T cells

Wu, Wen-Pyng; Tsai, Yi‐Giien; Lin, Tze–Yi; Wu, Ming‐Ju; Lin, Ching‐Yuang

doi:10.1186/s12882-017-0630-6

Cited by 26 publications

(22 citation statements)

References 35 publications

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“…But Tamassia noted that the human neutrophils are unable to express and produce IL-17A, IL-17B, or IL-17F in vitro ( 61 ). Our data show that IL-17A was mainly produced by CD4 + Tcell, rather than F4/80 + macrophages in UUO mice, which was consistent with previous reports ( 55 , 62 ).…”

Section: Discussionsupporting

confidence: 94%

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

et al. 2018

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Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80+macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy.

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Section: Discussionsupporting

confidence: 94%

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

et al. 2018

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“…From a mechanistic point of view, increasing evidence has suggested that HDAC3-deficient macrophages upon LPS stimulation could not activate almost half of the inflammatory gene expression 62 . For instance, it was reported that HDAC inhibition by TSA treatment and vorinostat impedes the conversion of regulatory T cells (Tregs) into IL-17 + Tregs 12,63 . This led us to hypothesize the effect of PPL on modulating HDAC expression.…”

Section: Discussionmentioning

confidence: 99%

“…An important epigenetic phenomenon in macrophages is the transient inflammatory stimulus-mediated changes that include histone deacetylase (HDAC) activation, which increases the production of pro-inflammatory cytokines in wide disease models, including septic shock, acute respiratory distress syndrome, renal fibrosis, and rheumatoid arthritis, where abrogation of HDAC activity reduced inflammatory cytokines [10][11][12] . Moreover, HDAC inhibition was found to suppress the polarization of T helper type 17 (Th17) cells and STAT3 inhibition 13 , while HDAC3 inhibition reduced TNF-α, with a concomitant increase in the acetylation of p65, which has been suggested to play a key role in attenuating IκΒαmediated NF-κΒ transcriptional activity [14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation

et al. 2020

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Psoriasis is an autoimmune skin disease, where chronic immune responses due to exaggerated cytokine signaling, abnormal differentiation, and evasion of keratinocytes apoptosis plays a crucial role in mediating abnormal keratinocytes hyperproliferation. From the therapeutic perspective, the molecules with strong anti-proliferative and anti-inflammatory properties could have tremendous relevance. In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROSmediated late apoptosis with loss of mitochondrial membrane potential. Besides, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation. Molecularly, inhibition of STAT3 and Akt signaling was observed with a decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression. Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly. Furthermore, prominent anti-inflammatory effects were observed by inhibition of lipopolysaccharide (LPS)/Imiquimod (IMQ)-induced p65 NF-κB signaling cascade and strongly inhibited the production of cytokine storm involved in psoriasis-like skin inflammation, thus led to the restoration of normal epidermal architecture with reduction of epidermal hyperplasia and splenomegaly. In addition, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1-4) and class II (HDAC6) evaluated by immunoblotting and HDAC enzyme assay kit. In addition, our results show that PPL effectively inhibits the nuclear translocation of p65 and a histone modulator HDAC3, thus sequestered in the cytoplasm of macrophages. Furthermore, PPL effectively enhanced the protein-protein interactions of HDAC3 and p65 with IκBα, which was disrupted by LPS stimulation and were evaluated by Co-IP and molecular modeling. Collectively, our findings indicate that piperlongumine may serve as an anti-proliferative and anti-inflammatory agent and could serve as a potential therapeutic option in treating psoriasis.

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“…This may be a consequence of the fact that most rodent models of diabetes do not develop late-stage fibrotic changes that are typically associated with GFR decline [ 94 ]. That being said, broad-spectrum, class-specific or isoform-specific HDAC inhibitors have been reported to have anti-fibrotic effects in non-diabetic rodent models of renal fibrosis, including the unilateral ureteral obstruction model [ 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ] and the rat remnant kidney model [ 88 ]. Given that common pathogenetic mechanisms are often shared during the development of renal fibrosis, regardless of the etiology, it could be postulated that HDAC inhibition may confer similar benefits on later stage renal decline.…”

Section: Future Directionsmentioning

confidence: 99%

Histone Deacetylase Inhibitors and Diabetic Kidney Disease

Hadden

Advani

2018

IJMS

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Despite recent clinical trial advances and improvements in clinical care, kidney disease due to diabetes remains the most common cause of chronic kidney failure worldwide. In the search for new treatments, recent attentions have turned to drug repurposing opportunities, including study of the histone deacetylase (HDAC) inhibitor class of agents. HDACs are a group of enzymes that remove functional acetyl groups from histone and non-histone proteins and they can affect cellular function through both epigenetic and non-epigenetic means. Over the past decade, several HDAC inhibitors have been adopted into clinical practice, primarily for the treatment of hematological malignancy, whereas other existing therapies (for instance valproate) have been found to have HDAC inhibitory effects. Here we review the current HDAC inhibitors in the clinic and under development; the literature evidence supporting the renoprotective effects of HDAC inhibitors in experimental diabetic kidney disease; and the adverse effect profiles that may prevent existing therapies from entering the clinic for this indication. Whereas recent research efforts have shed light on the fundamental actions of HDACs in the diabetic kidney, whether these efforts will translate into novel therapies for patients will require more specific and better-tolerated therapies.

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The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3+IL-17+ T cells

Cited by 26 publications

References 35 publications

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation

Histone Deacetylase Inhibitors and Diabetic Kidney Disease

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