Mastitis is one of the most serious diseases in humans and animals, especially in the modern dairy industry. Seeking safe and effective mastitis prevention strategies is urgent since food safety and drug residues in milk remain an enormous concern, despite the contribution of antibiotics to control mastitis. Kynurenic acid (KYNA), derived from the kynurenine pathway of tryptophan metabolism, has been shown to exhibit anti-inflammatory and immunomodulatory effects in many diseases. Recently, it was reported that impaired KYNA levels were associated with mastitis. However, the physiological role of KYNA in mastitis has not yet been elucidated. Therefore, the aim of this study was to investigate the protective role of KYNA in pathogen-induced mastitis in mice, as well as the underlying mechanism of this effect. We first evaluated the effects of KYNA on LPS-induced mastitis in mice. Additionally, the underlying anti-inflammatory mechanism of KYNA was investigated in mammary epithelial cells (MMECs). Furthermore, we examined the effects of KYNA on S. aureus and E. coli induced mastitis in mice. Our results demonstrated that KYNA alleviated LPS-induced mastitis by reducing inflammatory responses and enhancing blood-milk barrier integrity. The fundamental mechanisms involved the inhibition of NF-κB and activation of Nrf2/Ho-1, which is probably mediated by G protein-coupled receptor 35 but not aryl hydrocarbon receptor. Notably, KYNA also protected against S. aureus and E. coli induced mastitis in mice. In conclusion, our results highlight the role of KYNA in mastitis and serve as a basis for using endogenous metabolite as a novel preventative or therapeutic strategy for disease intervention.

乳腺炎是人类和动物中最严重的疾病之一，尤其是在现代乳业中。尽管抗生素有助于控制乳腺炎，但由于食品安全和牛奶中的药物残留仍然是一个巨大的问题，因此迫切需要寻求安全有效的乳腺炎预防策略。犬尿氨酸 (KYNA) 来源于色氨酸代谢的犬尿氨酸途径，已被证明在许多疾病中具有抗炎和免疫调节作用。最近，有报道称 KYNA 水平受损与乳腺炎有关。然而，KYNA在乳腺炎中的生理作用尚未阐明。因此，本研究的目的是研究 KYNA 在病原体诱导的小鼠乳腺炎中的保护作用，以及这种作用的潜在机制。我们首先评估了 KYNA 对 LPS 诱导的小鼠乳腺炎的影响。此外，还在乳腺上皮细胞 (MMEC) 中研究了 KYNA 的潜在抗炎机制。此外，我们检查了 KYNA 对金黄色葡萄球菌和大肠杆菌诱导小鼠乳腺炎。我们的结果表明，KYNA 通过减少炎症反应和增强血-乳屏障完整性来缓解 LPS 诱导的乳腺炎。基本机制涉及抑制 NF-κB 和激活 Nrf2/Ho-1，这可能由 G 蛋白偶联受体 35 介导，而不是芳烃受体介导。值得注意的是，KYNA 还可以预防金黄色葡萄球菌和大肠杆菌诱导的小鼠乳腺炎。总之，我们的结果强调了 KYNA 在乳腺炎中的作用，并作为使用内源性代谢物作为疾病干预的新型预防或治疗策略的基础。