CD5L Promotes Efferocytosis and Resolution of Retinal Ischemic Injury

ABSTRACT: Ischemia-induced retinopathy is a defining characteristic of prevalent ocular conditions such as diabetic retinopathy and central retinal artery and vein occlusions. Current therapeutic interventions for ischemic retinopathies have shown limited efficacy, highlighting the need for a better understanding of the underlying mechanisms. Histone deacetylase 3 (HDAC3) is a member of the class I histone deacetylase enzyme family, which participates in regulating gene expression by removing acetyl groups from histone proteins. We have recently uncovered the role of myeloid HDAC3 as a potential key inhibitor of efferocytosis following retinal ischemia, the process by which myeloid cells clear dead cells to facilitate tissue repair. Here, we investigated the underlying mechanism by which HDAC3 inhibits efferocytosis through regulating the CD5 antigen-like (CD5L)/cluster of differentiation 36 (CD36) axis, which was identified through RNA-sequencing. We utilized myeloid-specific HDAC3 knockout (KO) mice in our in vivo studies and in vitro macrophage efferocytosis assays. To assess the role of CD5L in retinal injury, we subjected CD5L KO mice to ischemia-reperfusion (IR) and treated wild-type (WT) mice with recombinant CD5L. We evaluated retinal injury outcomes through retinal imaging, neurovascular assessments, and functional tests conducted in vivo. Additionally, we conducted in vitro studies to investigate the underlying mechanisms. RNA sequencing data identified CD5L as a pro-efferocytic molecule that is upregulated in HDAC3 knockout macrophages after exposure to apoptotic cells in vitro. Similarly, CD5L is also upregulated in the retinas of myeloid HDAC3 knockout mice following IR injury, where it colocalized with myeloid cells. HDAC3 suppresses CD5L transcription in an LXR-dependent manner. Experiments conducted with CD5L KO mice and treatment involving recombinant CD5L protein demonstrated a protective role for CD5L against retinal ischemic injury. Additionally, we found that CD36, a receptor for CD5L that facilitates the clearance of apoptotic cells, is upregulated in the retina myeloid cells following IR injury. In vitro experiments indicated that CD5L mediates efferocytosis via CD36.

ORGANISM(S): Mus musculus

PROVIDER: GSE301077 | GEO | 2026/03/19

REPOSITORIES: GEO