Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis

Abstract

In a previous paper, we reported that triptolide (TP), a commonly used immunomodulator, could attenuate cardiac hypertrophy. This present study aimed to further explore the inhibition of cardiac fibrosis by TP and the possible mechanism from the perspective of the NOD-like receptor protein 3 (NLRP3) inflammasome. Hematoxylin-eosin and Masson’s staining, immunohistochemistry, and immunofluorescence were performed to observe cardiac fibrotic changes in mice and mouse cardiac fibroblasts (CFs). The Western blot, colocalization, and immunoprecipitation were applied to detect protein expression and interactions. Results suggested that TP dose-dependently inhibited cardiac fibrosis induced by isoproterenol and collagen production of CFs induced by angiotensin II. TP exhibited an antifibrotic effect via inhibiting activation of the NLRP3 inflammasome, which sequentially decreased IL-1β maturation, myeloid differentiation factor 88 (MyD88)-related phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase 1/2 (ERK1/2), and TGF-β1/Smad signaling, and ultimately resulted in less collagen production. Moreover, TP showed no antifibrotic effect in Nlrp3-knockout CFs. Notably, TP inhibited the expression of NLRP3 and apoptosis-associated speck-like proteins containing a caspase recruitment domain (ASC) as well as inflammasome assembly, by interrupting the NLRP3-ASC interaction to inhibit inflammasome activation. Finally, TP indeed inhibited the NLRP3-TGFβ1-Smad pathway in vivo. Conclusively, TP was found to play a dual role in interrupting the activation of the NLRP3 inflammasome to attenuate cardiac fibrosis.

Immunomodulatory Effects of Diterpenes and Their Derivatives Through NLRP3 Inflammasome Pathway: A Review

“…This effect (a) enhanced cardiac diastolic and systolic functions, (b) activated the pro-fibrotic tumor growth factor 1 beta (TGF-1β) pathway, (c) suppressed the NLRP3 inflammasome and inflammatory mediators of IL-1β, IL-18, MCP-1, and vascular cell adhesion molecule-1 (VCAM-1), and (d) dose-dependently inhibited macrophage infiltration (29). In a recent study, it has been found to inhibit the NLRP3-TGF1β-Smad pathway, suggesting that this compound might be an alternative option for cardiac fibrosis via targeting the NLRP3 inflammasome (30). Furthermore, it down-regulated NLRP3 by targeting hsa-miR-20b in male C57BL/6 mice and in THP-1 cells (31).…”

Nucleotide-Binding Oligomerization Domain-Like Receptor 3 Deficiency Attenuated Isoproterenol-Induced Cardiac Fibrosis via Reactive Oxygen Species/High Mobility Group Box 1 Protein Axis

“…Cardiac fibrosis is a common feature of many pathological cardiac remodeling. Numerous studies have shown that inhibition of the NLRP3 inflammasome pathway exhibited anti-fibrosis effects (Gan et al, 2018;Qiu et al, 2018;Wan et al, 2018;Pan et al, 2019;Gao et al, 2019). However, recently, Li F. et al (2018) found that NLRP3 deficiency exacerbates cardiac fibrosis and inflammation induced by pressure overload, which was contradictory with the previous studies.…”

The Role of NLRP3 in The Prognosis and Immune Infiltrates of Skin Cutaneous Melanoma (SKCM)

“…The NLRP3 in ammasome comprises the sensor molecule NLRP3, the adaptor protein ASC, and pro-caspase 1 [26]. Xi-Chun Pan et al [27] found that TP had no in uence on NLRP3 or ASC oligomerization, but that it could inhibit NLRP3 and ASC expression, as well as NLRP3-ASC interactions, to inhibit in ammasome assembly. Melanoma research demonstrated that the development of cancer cells was inhibited by reduced in ammasome and IL-1β expression [28].…”