Inhibition of NLRP3 inflammasome-mediated pyroptosis in macrophage by cycloastragenol contributes to amelioration of imiquimod-induced psoriasis-like skin inflammation in mice

Deng, Guoliang; Chen, Wenjun; Wang, Peng; Zhan, Tianying; Zheng, Wei; Gu, Zhengbing; Wang, Xiaomei; Ji, Xiaoyun; Sun, Yang

doi:10.1016/j.intimp.2019.105682

Cited by 68 publications

(40 citation statements)

References 50 publications

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“…In the present study, MHP1-AcN was shown to inhibit TLR7/8 agonist-induced IL-6 production in RAW 264.7 cells and in a mouse model of psoriasis at the early stage of disease. Compared to a recent study showing that an approximately 40% reduction in IL-6 in mice treated with cycloastragenol resulted in better clinical outcomes 22 , a 71.1% decrease in serum IL-6 by MHP1- AcN at the early stage might be enough to be associated with better clinical outcomes. There is evidence supporting the beneficial effects of IL-6 inhibition in the treatment of psoriasis.…”

Section: Discussioncontrasting

confidence: 67%

Preventative effects of the partial RANKL peptide MHP1-AcN in a mouse model of imiquimod-induced psoriasis

Shimamura

Hayashi³

et al. 2019

Sci Rep

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We recently developed a partial peptide of receptor activator of nuclear factor-кB ligand (RANKL) known as microglial healing peptide 1 (MHP1-AcN), that inhibits Toll-like receptor (TLR)-related inflammation through RANKL/RANK signaling in microglia and macrophages without promoting osteoclast activation. The abnormal activation of TLRs contributes to the initiation and maintenance of psoriasis, which is a chronic inflammatory skin disease that involves the aberrant expression of proinflammatory cytokines and the subsequent dermal γδ T cell and T helper 17 (Th17) cell responses. The inhibition of TLR-mediated inflammation provides an important strategy to treat psoriasis. Here, we examined the preventative effects of MHP1-AcN in a mouse model of imiquimod (a TLR 7/8 agonist)-induced psoriasis. Topical imiquimod application induced psoriasis-like skin lesions on the ear and dorsal skin. Systemic administration of MHP1-AcN by daily subcutaneous injection significantly prevented the development of skin lesions, including erythema, scaling and thickening. Mice treated with MHP1-AcN showed reduced levels of skin Il6 mRNA at 32 h and reduced levels of Il23 and Il17a mRNA at d9. Serum levels of IL-6 and IL-23 were reduced at 32 h, and IL-17A was reduced at d9. These results indicated that MHP1-AcN could decrease imiquimod-induced IL-6, IL-23 and IL-17A production. MHP1-AcN is potentially an alternative treatment for psoriasis.

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Section: Discussioncontrasting

confidence: 67%

Preventative effects of the partial RANKL peptide MHP1-AcN in a mouse model of imiquimod-induced psoriasis

Shimamura

Hayashi³

et al. 2019

Sci Rep

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“…Similarly, a natural active compound from Astragalus membranaceus—cycloastragenol (CAG)—greatly ameliorated imiquimod- (IMQ-) induced psoriasiform dermatitis in mice by targeting regulation of proinflammatory macrophages (M1). CAG, on the one hand, obviously reduced the infiltration of M1 macrophages into psoriatic dermis; on the other hand, it in a dose-dependent mean lowered the level of proinflammatory cytokines (including IL-1 β , TNF- α , and IL-6) in murine psoriatic skin and serum [ 140 ]. In addition, naringenin, a flavonoid compound, has been shown in a psoriasis-like mouse model to mitigate skin inflammation through accelerating the reprogramming of macrophages from M1 to M2 [ 141 ].…”

Section: Treatment Hotlinementioning

confidence: 99%

Regulating the Polarization of Macrophages: A Promising Approach to Vascular Dermatosis

Peng

Xian

Liu

et al. 2020

Journal of Immunology Research

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Macrophages, a kind of innate immune cells, derive from monocytes in circulation and play a crucial role in the innate and adaptive immunity. Under the stimulation of the signals from local microenvironment, macrophages generally tend to differentiate into two main functional phenotypes depending on their high plasticity and heterogeneity, namely, classically activated macrophage (M1) and alternatively activated macrophage (M2). This phenomenon is often called macrophage polarization. In pathological conditions, chronic persistent inflammation could induce an aberrant response of macrophage and cause a shift in their phenotypes. Moreover, this shift would result in the alteration of macrophage polarization in some vascular dermatoses; e.g., an increase in proinflammatory M1 emerges from Behcet’s disease (BD), psoriasis, and systemic lupus erythematosus (SLE), whereas an enhancement in anti-inflammatory M2 appears in infantile hemangioma (IH). Individual polarized phenotypes and their complicated cytokine networks may crucially mediate in the pathological processes of some vascular diseases (vascular dermatosis in particular) by activation of T cell subsets (such as Th1, Th2, Th17, and Treg cells), deterioration of oxidative stress damage, and induction of angiogenesis, but the specific mechanism remains ambiguous. Therefore, in this review, we discuss the possible role of macrophage polarization in the pathological processes of vascular skin diseases. In addition, it is proposed that regulation of macrophage polarization may become a potential strategy for controlling these disorders.

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“…NLRP3 inflammasome has been implicated in the pathogenesis of several autoinflammatory conditions (17). Its role in psoriasis remains to be fully clarified, although several reports suggest its involvement (18,19). The inflammasome also plays a role in a number of psoriasis-related comorbidities such as metabolic syndrome, atherosclerosis, and cardiovascular disease (20).…”

Section: Introductionmentioning

confidence: 99%

Promoter Methylation Leads to Decreased ZFP36 Expression and Deregulated NLRP3 Inflammasome Activation in Psoriatic Fibroblasts

et al. 2021

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The mRNA-destabilizing protein tristetraprolin (TTP), encoded by the ZFP36 gene, is known to be able to end inflammatory responses by directly targeting and destabilizing mRNAs encoding pro-inflammatory cytokines. We analyzed its role in psoriasis, a disease characterized by chronic inflammation. We observed that TTP is downregulated in fibroblasts deriving from psoriasis patients compared to those deriving from healthy individuals and that psoriatic fibroblasts exhibit abnormal inflammasome activity compared to their physiological counterpart. This phenomenon depends on TTP downregulation. In fact, following restoration, TTP is capable of directly targeting for degradation NLRP3 mRNA, thereby drastically decreasing inflammasome activation. Moreover, we provide evidence that ZFP36 undergoes methylation in psoriasis, by virtue of the presence of long stretches of CpG dinucleotides both in the promoter and the coding region. Besides confirming that a perturbation of TTP expression might underlie the pathogenesis of psoriasis, we suggest that deregulated inflammasome activity might play a role in the disease alongside deregulated cytokine expression.

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Inhibition of NLRP3 inflammasome-mediated pyroptosis in macrophage by cycloastragenol contributes to amelioration of imiquimod-induced psoriasis-like skin inflammation in mice

Cited by 68 publications

References 50 publications

Preventative effects of the partial RANKL peptide MHP1-AcN in a mouse model of imiquimod-induced psoriasis

Preventative effects of the partial RANKL peptide MHP1-AcN in a mouse model of imiquimod-induced psoriasis

Regulating the Polarization of Macrophages: A Promising Approach to Vascular Dermatosis

Promoter Methylation Leads to Decreased ZFP36 Expression and Deregulated NLRP3 Inflammasome Activation in Psoriatic Fibroblasts

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