Non-caveolar caveolin - 1 in retinal Müller glia promotes innate immune responses.

Caveolae are specialized plasma membrane invaginations implicated in ocular diseases including primary open angle glaucoma, diabetic retinopathy and age-related macular degeneration. Caveolin - 1 (CAV1) typically functions within caveolae where it associates with a co-regulatory protein, CAVIN1 (also known as polymerase I and transcript release factor; PTRF), which is necessary for caveolae formation. However, CAV1 can also reside outside of caveolae in planar "scaffolds," though the function of this non-caveolar CAV1 remains unclear. Here we show that Müller glia, the major macroglial cells of the retina, abundantly express CAV1 with minimal CAVIN1/PTRF expression both in situ and in the MIO-M1 Müller glial cell line. Transmission electron microscopy confirmed that morphologically identifiable caveolae are virtually absent in Müller glia, indicating that CAV1 is predominantly non-caveolar. Transgenic CAVIN1/PTRF expression induced caveolae formation, demonstrating functional competence. Non-caveolar CAV1 in MIO-M1 Müller glia promoted Toll-like receptor - 4 (TLR4) signaling, as either CAV1 silencing or its sequestration into caveolae by CAVIN1/PTRF overexpression significantly suppressed lipopolysaccharide (LPS)-induced interleukin - 6 (IL - 6) upregulation through reduced NF-κB activation. Conversely, in human retinal endothelial cells (HRECs) where CAV1 predominantly localizes to caveolae, CAV1 silencing enhanced inflammatory responses. These results demonstrate that non-caveolar CAV1 in Müller glia promotes a pro-inflammatory phenotype that can be attenuated by CAV1 silencing or sequestration into caveolae, suggesting cell context-specific roles for CAV1 in inflammatory regulation with potential therapeutic implications for ocular inflammatory diseases.