Zhao Jiamin, Zhang Shuangyi, Gong Zhiguo, Mao Wei, Bao Wenhui, Li Qianru, Bai Yunjie, Gao Feifei, Feng Shuang
Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China.
Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
Cell Commun Signal. 2025 Jan 29;23(1):55. doi: 10.1186/s12964-025-02063-9.
Wound healing is a highly coordinated process driven by intricate molecular signaling and dynamic interactions between diverse cell types. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) has been implicated in the regulation of inflammation and tissue repair; however, its specific role in skin wound healing remains unclear. This study highlights the pivotal role of NLRP3 in effective skin wound healing, as demonstrated by delayed wound closure and altered cellular and molecular responses in NLRP3-deficient (NLRP3) mice. Histological analysis revealed impaired healing processes, accompanied by reduced expression of key inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E (PGE). Deficiencies in apoptosis were evident through altered expression of cysteine-aspartic acid protease 3 (Caspase-3), P53, and B-cell lymphoma-2 (Bcl-2). Furthermore, critical growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinase-9 (MMP-9) were significantly decreased at the excisional skin wound sites. Furthermore, using co-culture systems, we found that NLRP3 mediated the interaction between macrophages and myofibroblasts. Wild-type fibroblast-conditioned media (MFbCM) enhanced nitric oxide (NO), IL-6, and tumor necrosis factor-α (TNF-α) production in M1 macrophages and arginase activity, chitinase 3-like protein 1 (Ym1), and IL-10 expression in M2 macrophages, effects significantly diminished with NLRP3 MFbCM. Similarly, conditioned media from wild-type M1 or M2 macrophages promoted the expression of FGF-2, VEGF, and MMP-2 expression in myofibroblasts, which was attenuated when using NLRP3 macrophage-conditioned media. PGE levels were reduced in both NLRP3 macrophages and myofibroblasts. Supplementing NLRP3 conditioned media with PGE partially restored the impaired functions, suggesting that PGE acts as a downstream mediator of NLRP3-regulated macrophage-myofibroblast interactions. These findings indicate that NLRP3 is a key regulator of skin wound healing, facilitating macrophage-myofibroblast communication.
伤口愈合是一个高度协调的过程，由复杂的分子信号传导以及不同细胞类型之间的动态相互作用驱动。含NOD样受体吡咯结构域蛋白3（NLRP3）与炎症调节和组织修复有关；然而，其在皮肤伤口愈合中的具体作用仍不清楚。本研究强调了NLRP3在有效的皮肤伤口愈合中的关键作用，这在NLRP3缺陷（NLRP3-/-）小鼠的伤口愈合延迟以及细胞和分子反应改变中得到了证明。组织学分析显示愈合过程受损，同时关键炎症介质的表达减少，包括白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和前列腺素E（PGE）。通过半胱天冬酶-3（Caspase-3）、P53和B细胞淋巴瘤-2（Bcl-2）表达的改变，凋亡缺陷明显。此外，在切除性皮肤伤口部位，关键生长因子如血管内皮生长因子（VEGF）、表皮生长因子（EGF）和基质金属蛋白酶-9（MMP-9）显著减少。此外，使用共培养系统，我们发现NLRP3介导了巨噬细胞与肌成纤维细胞之间的相互作用。野生型成纤维细胞条件培养基（MFbCM）增强了M1巨噬细胞中一氧化氮（NO）、IL-6和肿瘤坏死因子-α（TNF-α）的产生，以及M2巨噬细胞中的精氨酸酶活性、几丁质酶3样蛋白1（Ym1）和IL-10表达，而NLRP3-/- MFbCM的这些作用显著减弱。同样，来自野生型M1或M2巨噬细胞的条件培养基促进了肌成纤维细胞中FGF-2、VEGF和MMP-2的表达，而使用NLRP3-/-巨噬细胞条件培养基时这种促进作用减弱。NLRP3-/-巨噬细胞和肌成纤维细胞中的PGE水平均降低。用PGE补充NLRP3-/-条件培养基可部分恢复受损功能，表明PGE作为NLRP3调节的巨噬细胞-肌成纤维细胞相互作用的下游介质发挥作用。这些发现表明NLRP3是皮肤伤口愈合的关键调节因子，促进巨噬细胞-肌成纤维细胞的通讯。
