2,4-Dimethoxy-6-Methylbenzene-1,3-diol, a Benzenoid From Antrodia cinnamomea, Mitigates Psoriasiform Inflammation by Suppressing MAPK/NF-κB Phosphorylation and GDAP1L1/Drp1 Translocation

Chuang, Shih-Yi; Chen, Chi-Yuan; Yang, Shih-Chun; Alalaiwe, Ahmed; Lin, Cheng-Kuo; Fang, Jia‐You

doi:10.3389/fimmu.2021.664425

Cited by 10 publications

(7 citation statements)

References 61 publications

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“…To further confirm if the aforementioned influence of CFT073 wt on polarization of macrophages was caused by TcpC, rTcpC was prepared and its effects on macrophage polarization were also examined. In accordance with previous reports [ 27 , 31 , 32 ], LPS + IFN-γ significantly induced the expression of M1 markers CD80 and CD86, and IL-4 treatment promoted the expression of M2 markers CD163 and CD206 in both THP-1 and J774A.1 macrophage cell lines. However, 4 μg/mL rTcpC treatment profoundly attenuated LPS + IFN-γ=induced expression of CD80 and CD86 ( Figure 4 A–D), while promoting CD163 and CD206 expression ( Figure 4 E–H).…”

Section: Resultssupporting

confidence: 93%

“…It was reported that complete polarization of macrophages to the M1 type requires activation of the MAPK and NF-κB signaling pathways [ 19 , 27 , 31 , 61 ], and M2 macrophage polarization requires activation of the STAT signaling pathway [ 62 , 63 ]. To explore the signal transduction pathways underlying the regulatory effects of TcpC on M1/M2 polarization, the influence of TcpC on MAPK/NF-κB and Akt/STAT pathways was examined.…”

Section: Discussionmentioning

confidence: 99%

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TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Fang

et al. 2022

Cells

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TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Fang

et al. 2022

Cells

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“…Our CM functional analyses further show that Gm41664 increases CM apoptosis by regulating the novel miR-150/GDAP1L1 axis. GDAP1L1 is conserved in vertebrates and is involved in the mitochondrial fission [ 42 ]. However, nothing is known about the cardiovascular roles and regulatory mechanisms of GDAP1L1.…”

Section: Discussionmentioning

confidence: 99%

“…Ganglioside Induced Differentiation Associated Protein 1 Like 1 (GDAP1L1) is a regulator of mitochondrial fission. Mitochondrial fission is required for maintaining mitochondrial functions including apoptosis [ 42 ]. GDAP1L1 is mainly expressed in the central nervous system [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome

et al. 2022

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The β1-adrenergic receptor (β1AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β1AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by β-arrestin-mediated β1AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues cardiac dysfunction in mice bearing CM-specific abrogation of β-arrestin-mediated β1AR signaling. Using CM-specific transgenic (TG) mice expressing a mutant β1AR (G protein-coupled receptor kinase [GRK]–β1AR that exhibits impairment in β-arrestin-mediated β1AR signaling), we first generate a novel double TG mouse line overexpressing miR-150. We demonstrate that miR-150 is sufficient to improve cardiac dysfunction in CM-specific GRK–β1AR TG mice following chronic catecholamine stimulation. Our genome-wide circular RNA, long noncoding RNA (lncRNA), and mRNA profiling analyses unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for beneficial actions of β1AR/β-arrestin signaling or miR-150. We further show that lncRNA Gm41664 and GDAP1L1 are direct novel upstream and downstream regulators of miR-150. Lastly, CM protective actions of miR-150 are attributed to repressing pro-apoptotic GDAP1L1 and are mitigated by pro-apoptotic Gm41664. Our findings support the idea that miR-150 contributes significantly to β1AR/β-arrestin-mediated cardioprotection by regulating unique ncRNA and gene signatures in CMs.

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“…While macrophages are shown to have a high TNF expression [ 19 ], the activation of TLRs can trigger the production of TNFα in macrophages [ 20 ]. IL-23, having a crucial role in psoriasis initiation [ 21 ], is capable of evoking IL-6-dependent cytokine release and epidermal thickening [ 22 ]. Furthermore, both TNF-α and IL-6 can induce IL-24 production in psoriasis [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Psoriasiform Inflammation Is Associated with Mitochondrial Fission/GDAP1L1 Signaling in Macrophages

Alalaiwe

Chen

Chang

et al. 2021

IJMS

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While psoriasis is known as a T cell- and dendritic cell-driven skin inflammation disease, macrophages are also reported to play some roles in its development. However, the signaling pathway of activated macrophages contributing to psoriasis is not entirely understood. Thus, we aimed to explore the possible mechanisms of how macrophages initiate and sustain psoriasis. The differentiated THP1 cells, stimulated by imiquimod (IMQ), were utilized as the activated macrophage model. IMQ was also employed to produce psoriasis-like lesions in mice. A transcriptomic assay of macrophages revealed that the expressions of pro-inflammatory mediators and GDAP1L1 were largely increased after an IMQ intervention. The depletion of GDAP1L1 by short hairpin (sh)RNA could inhibit cytokine release by macrophages. GDAP1L1 modulated cytokine production by activating the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways. Besides GDAP1L1, another mitochondrial fission factor, Drp1, translocated from the cytosol to mitochondria after IMQ stimulation, followed by the mitochondrial fragmentation according to the immunofluorescence imaging. Clodronate liposomes were injected into the mice to deplete native macrophages for examining the latter’s capacity on IMQ-induced inflammation. The THP1 cells, with or without GDAP1L1 silencing, were then transplanted into the mice to monitor the deposition of macrophages. We found a significant THP1 accumulation in the skin and lymph nodes. The silencing of GDAP1L1 in IMQ-treated animals reduced the psoriasiform severity score from 8 to 2. After depleting GDAP1L1, the THP1 recruitment in the lymph nodes was decreased by 3-fold. The skin histology showed that the GDAP1L1-mediated macrophage activation induced neutrophil chemotaxis and keratinocyte hyperproliferation. Thus, mitochondrial fission can be a target for fighting against psoriatic inflammation.

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2,4-Dimethoxy-6-Methylbenzene-1,3-diol, a Benzenoid From Antrodia cinnamomea, Mitigates Psoriasiform Inflammation by Suppressing MAPK/NF-κB Phosphorylation and GDAP1L1/Drp1 Translocation

Cited by 10 publications

References 61 publications

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome

Psoriasiform Inflammation Is Associated with Mitochondrial Fission/GDAP1L1 Signaling in Macrophages

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