Ueno Hiroki, Hattori Takaaki, Chi Hsi-Hua, Miyabe Yoshishige, Murayama Masanori A
Department of Immunology and Parasitology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
Exp Anim. 2025 Jan 10;74(1):58-65. doi: 10.1538/expanim.24-0063. Epub 2024 Aug 6.
The dense nerve and thin vascular structure of the corneal tissue provide the refractive function in healthy eyes. Diabetes mellitus causes ocular complications including corneal opacification because of corneal nerve degeneration. Diabetic neurotrophic keratopathy is characterized by reduced corneal sensitivity, delayed corneal wound healing, and nerve degeneration. Neurotization and vascularization inhibit each other in the cornea. Macrophages contribute to the corneal neovascularization. To investigate the role of macrophage in neurotrophic keratopathy, clodronate liposome was subconjunctivally injected into diabetic db/db mice with neurotrophic keratopathy. The clodronate liposome treatment decreased F4/80 macrophage infiltration into the corneal epithelium, and improved corneal nerve involvement in diabetic db/db mice. Furthermore, we found that Il1b and Il34 mRNA expression was increased in the corneal epithelium of clodronate-treated diabetic db/db mice. These cytokines contribute to the maintenance of nerve tissues via microglia and nerve regeneration; however, their role in corneal nerve involvement remains unknown. Notably, the intraocular injection of recombinant IL-1β and IL-34 promoted nerve regeneration in the cornea of diabetic db/db mice. These results suggest that clodronate liposome treatment contributes to nerve regeneration during corneal involvement via IL-1β and IL-34 signaling.
角膜组织密集的神经和稀疏的血管结构为健康眼睛提供屈光功能。糖尿病会引发眼部并发症，包括因角膜神经变性导致的角膜混浊。糖尿病性神经营养性角膜病变的特征是角膜敏感性降低、角膜伤口愈合延迟和神经变性。在角膜中，神经化和血管化相互抑制。巨噬细胞促进角膜新生血管形成。为了研究巨噬细胞在神经营养性角膜病变中的作用，将氯膦酸盐脂质体结膜下注射到患有神经营养性角膜病变的糖尿病db/db小鼠体内。氯膦酸盐脂质体治疗减少了F4/80巨噬细胞向角膜上皮的浸润，并改善了糖尿病db/db小鼠的角膜神经受累情况。此外，我们发现氯膦酸盐处理的糖尿病db/db小鼠角膜上皮中Il1b和Il34 mRNA表达增加。这些细胞因子通过小胶质细胞和神经再生有助于神经组织的维持；然而，它们在角膜神经受累中的作用仍然未知。值得注意的是，眼内注射重组IL-1β和IL-34可促进糖尿病db/db小鼠角膜中的神经再生。这些结果表明，氯膦酸盐脂质体治疗通过IL-1β和IL-34信号通路在角膜受累期间有助于神经再生。
