Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
FASEB J. 2021 Feb;35(2):e21315. doi: 10.1096/fj.202002135R.
Cataracts are a common consequence of aging; however, pathogenesis remains poorly understood. Here, we observed that after 3 months of age mice lacking the G protein-coupled leukocyte chemotactic receptor Fpr1 (N-formyl peptide receptor 1) began to develop bilateral posterior subcapsular cataracts that progressed to lens rupture and severe degeneration, without evidence of either systemic or local ocular infection or inflammation. Consistent with this, Fpr1 was detected in both mouse and human lens in primary lens epithelial cells (LECs), the only cell type present in the lens; however, expression was confined to subcapsular LECs located along the anterior hemispheric surface. To maximize translucency, LECs at the equator proliferate and migrate posteriorly, then differentiate into lens fiber cells by nonclassical apoptotic signaling, which results in loss of nuclei and other organelles, including mitochondria which are a rich source of endogenous N-formyl peptides. In this regard, denucleation and posterior migration of LECs were abnormal in lenses from Fpr1 mice, and direct stimulation of LECs with the prototypic N-formyl peptide agonist fMLF promoted apoptosis. Thus, Fpr1 is repurposed beyond its immunoregulatory role in leukocytes to protect against cataract formation and lens degeneration during aging.
白内障是衰老的常见后果；然而，其发病机制仍不清楚。在这里，我们观察到，在 3 个月大后，缺乏 G 蛋白偶联白细胞趋化受体 Fpr1（N-甲酰肽受体 1）的小鼠开始出现双侧后囊下白内障，随后发展为晶状体破裂和严重退化，没有全身或局部眼部感染或炎症的证据。与此一致的是，Fpr1 在小鼠和人晶状体的初级晶状体上皮细胞（LEC）中均有检测到，LEC 是晶状体中唯一存在的细胞类型；然而，表达仅限于沿前半球表面的囊下 LEC。为了最大限度地提高透明度，赤道处的 LEC 增殖并向后迁移，然后通过非经典凋亡信号分化为晶状体纤维细胞，导致细胞核和其他细胞器（包括富含内源性 N-甲酰肽的线粒体）的丢失。在这方面，Fpr1 小鼠晶状体中的 LEC 去核和向后迁移异常，并且用原型 N-甲酰肽激动剂 fMLF 直接刺激 LEC 可促进细胞凋亡。因此，Fpr1 的作用不仅限于其在白细胞中的免疫调节作用，还可以防止衰老过程中白内障的形成和晶状体退化。
