Targeting the HDAC6‐Cilium Axis Ameliorates the Pathological Changes Associated with Retinopathy of Prematurity

Abstract

ROP) is one of the leading causes of childhood visual impairment and blindness. However, there are still very few effective pharmacological interventions for ROP. Histone deacetylase 6 (HDAC6)-mediated disassembly of photoreceptor cilia has recently been implicated as an early event in the pathogenesis of ROP. Herein it is shown that enhanced expression of HDAC6 by intravitreal injection of adenoviruses encoding HDAC6 induces the typical pathological changes associated with ROP in mice, including disruption of the membranous disks of photoreceptor outer segments and a decrease in electroretinographic amplitudes. Hdac6 transgenic mice exhibit similar ROP-related defects in retinal structures and functions and disassembly of photoreceptor cilia, whereas Hdac6 knockout mice are resistant to oxygen change-induced retinal defects. It is further shown that blocking HDAC6-mediated cilium disassembly by intravitreal injection of small-molecule compounds protect mice from ROP-associated retinal defects. The findings indicate that pharmacological targeting of the HDAC6-cilium axis may represent a promising strategy for the prevention of ROP.

Cytoskeletal networks in primary cilia: Current knowledge and perspectives

“…A growing number of cytoskeleton-associated proteins are now recognized as involved in cilium formation by regulating actin or microtubule network dynamics. Notably, our previous work revealed a critical role for tubulin deacetylase HDAC6 in photoreceptorconnecting cilia, suggesting potential value for HDAC6-targeting drugs for the prevention of retinopathy of prematurity (Ran et al, 2020;Ran et al, 2022). There is also increasing recognition of the critical involvement of many actin-binding proteins in primary ciliogenesis, such as the Arp2/3 complex (Afanasyeva et al, 2022), neuronal Wiskott-Aldrich syndrome protein (N-WASP) (Drummond et al, 2018), formin (Copeland et al, 2018), and myosin-VI (Magistrati et al, 2022).…”

Primary cilium‐mediated signaling cascade suppresses age‐related biliary fibrosis

“…The embedded samples were then cut into frozen sections with a thickness of 8 µm. H&E or Sirius red staining were performed on the paraffin‐embedded sections, following the standard protocols established in our laboratory as described previously (Ran et al, 2022). For immunofluorescence staining, the slides were fixed once again with 4% paraformaldehyde for 20 min, permeabilized with 0.5% Triton X‐100 in phosphate‐buffered saline for 20 min, and blocked with 4% bovine serum albumin for 1 h. The slides were then incubated overnight at 4°C with the appropriate dilution of antibodies against CK19, ARL13B, or Ace‐tubulin.…”

CCL2‐CCR2 signaling axis in obesity and metabolic diseases

“…Macrophages assume a critical role in the landscape of obesity, serving as catalysts for the inflammatory processes ensconced within adipose tissue. While the precise mechanisms governing macrophage infiltration into adipose tissue remain partially elucidated, it appears that the chemokine CCL2, emanating from adipocytes, stands as a pivotal factor in orchestrating the recruitment of macrophages to sites of inflammation and injury (Charo & Ransohoff, 2006; Ran et al, 2022; Tan et al, 2023). Notably, the significance of CCL2 transcends the realm of obesity, as it has been implicated in the pathogenesis of various diseases, encompassing atherosclerosis, diabetes, and cardiovascular disorders (Gunn et al, 1997; Niu & Kolattukudy, 2009; J. Yang et al, 2023).…”