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Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing.

ABSTRACT: Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1β, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.

SUBMITTER: Lv D

PROVIDER: S-EPMC10439185 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing.

Lv Dongming D Cao Xiaoling X Zhong Li L Dong Yunxian Y Xu Zhongye Z Rong Yanchao Y Xu Hailin H Wang Zhiyong Z Yang Hao H Yin Rong R Chen Miao M Ke Chao C Hu Zhicheng Z Deng Wuguo W Tang Bing B

Cell reports. Medicine 20230721 8

Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas re ...[more]

PMID: 37480849

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Project description:The aim of this study was to evaluate the therapeutic effects of Bletilla striata polysaccharide (BSP) on wound healing in diabetes mellitus (DM) and to explore the underlying mechanisms. DM mouse models were induced by high fat-diet feeding combined with low-dose streptozocin injection. To establish diabetic foot ulcer (DFU) models, DM mice were wounded on the dorsal surface. Subsequently, mice were treated with vehicle or BSP for 12 days and wound healing was monitored. The effects of BSP on the production of interleukin-1β (IL-1β), tumor necrosis factor-α, macrophages infiltration, angiogenesis, the activation of nucleotide-binding and oligomerization (NACHT) domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome, and insulin sensitivity in wound tissues were subsequently evaluated. Separated- and cultured- bone marrow-derived macrophages (BMDMs) and cardiac microvascular endothelial cells (CMECs) were isolated from mice and used to investigate the effects of BSP on cell viability, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation and insulin sensitivity in vitro following exposure to high glucose (HG). BSP administration accelerated diabetic wound healing, suppressed macrophage infiltration, promoted angiogenesis, suppressed NLRP3 inflammasome activation, decreased IL-1β secretion, and improved insulin sensitivity in wound tissues in DM mice. In vitro, co-treatment with BSP protected against HG-induced ROS generation, NLRP3 inflammasome activation, and IL-1β secretion in BMDMs, and improved cell viability and decreased ROS levels in CMECs. Moreover, in HG exposed BMDMs-CMECs cultures, BSP treatment suppressed NLRP3 inflammasome activation and IL-1β secretion in BMDMs, and improved cell viability and insulin sensitivity in CMECs. Furthermore, treatment with IL-1β almost completely suppressed the beneficial effects of BSP on the NLRP3 inflammasome, IL-1β secretion, and insulin sensitivity in HG-treated BMDMs-CMECs. BSP promotes DFU healing through inhibition of the HG-activated NLRP3 inflammasome.

Project description:Introduction: Chronic, non-healing skin wounds such as diabetic foot ulcers (DFUs) are common in patients with type 2 diabetes mellitus (T2DM) and often result in limb amputation and even death. However, mechanisms by which T2DM and inflammation negatively impact skin wound healing remains poorly understood. Here we investigate a mechanism by which an excessive level of chemokine CCL28, through its receptor CCR10, impairs wound healing in patients and mice with T2DM. Methods & Results: Firstly, a higher level of CCL28 was observed in skin and plasma in both patients with T2DM, and in obesity-induced type 2 diabetic db/db mice. Compared with WT mice, adipose tissue from db/db mice released 50% more CCL28, as well as 2- to 3-fold more IL-1β, IL-6, and TNF-α, and less VEGF, as determined by ELISA measurements. Secondly, overexpression of CCL28 with adenovirus (Adv-CCL28) caused elevation of proinflammatory cytokines as well as CCR10 expression and also reduced eNOS expression in the dorsal skin of WT mice as compared with control Adv. Thirdly, topical application of neutralizing anti-CCL28 Ab dose-dependently accelerated wound closure and eNOS expression, and decreased IL-6 level, with an optimal dose of 1 μg/wound. In addition, mRNA levels of eNOS and anti-inflammatory cytokine IL-4 were increased as shown by real-time RT-PCR. The interaction between eNOS and CCR10 was significantly reduced in diabetic mouse wounds following application of the optimal dose of anti-CCL28 Ab, and eNOS expression increased. Finally, enhanced VEGF production and increased subdermal vessel density as indicated by CD31 immunostaining were also observed with anti-CCL28 Ab. Discussion: Taken together, topical application of neutralizing anti-CCL28 Ab improved dorsal skin wound healing by reducing CCR10 activation and inflammation in part by preventing eNOS downregulation, increasing VEGF production, and restoring angiogenesis. These results indicate anti-CCL28 Ab has significant potential as a therapeutic strategy for treatment of chronic non-healing diabetic skin wounds such as DFUs.

Dataset Information

Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing.

Publications

Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing.

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