Abstract
Purpose:
Caveolin-1, (Cav-1) the primary scaffolding protein of caveolae membrane domains is proposed to modulate inflammatory signaling. In Müller glia, Cav-1 is upregulated during inflammation and downregulated during retinal degeneration. As proinflammatory and neuroprotective signaling significantly overlap in cytokines and downstream signaling pathways [e.g., interleukin-6 (IL-6) family neurocytokine signaling], we hypothesized that Cav-1 may modulate both inflammatory and neuroprotective signaling in the retina. In the present study, we tested this hypothesis.
Methods:
To assess inflammatory signaling, Cav-1 knockout (KO) and control mice were challenged by intravitreal injection of lipopolysaccharide, and cytokine/chemokine levels were measured by multiplex immunoassays. To induce secondary retinal degeneration, retina-specific Cav-1 KO mice and controls were injected intraperitoneally with sodium iodate (NaIO3) to induce primary RPE damage and a secondary retinal injury response. Retinal degeneration/damage was assessed by histology, immunohistochemistry, and Western blotting. Intravitreal injection of IL-6 family cytokine, leukemia inhibitory factor (LIF) was used to assess the effect of Cav-1 on gp130 receptor activation.
Results:
Following inflammatory challenge, protein levels of IL-6, monocyte chemotactic protein-1/CCL2, CXCL1/KC, and IL-1b were significantly reduced in retinal extracts from Cav-1 KO compared to control mice. Because IL-6 family cytokines (e.g., LIF, ciliary neurotrophic factor, oncostatin M, and IL-6) play important roles in retinal neuroprotection via STAT3 signaling downstream of the gp130 receptor, we predicted that dampened cytokine production would result in reduced downstream neuroprotective signaling. At both 3 and 7 days after NaIO3 induced RPE damage, STAT3 activation was significantly blunted in Cav-1-deficient retinas, supporting our hypothesis. Furthermore, STAT3 activation in response to intravitreal injection of LIF was not different in Cav-1-deficient retinas, indicating that Cav-1 functions upstream of the gp130 receptor.
Conclusions:
Our data demonstrate that Cav-1 plays a role in stress induced expression of protective and inflammatory cytokines, but is not necessary for gp130 or STAT3 activation, which are downstream of IL-6 cytokines. This suggests that Cav-1 plays a role in signaling pathways that control cytokine induction or secretion.
Keywords: 615 neuroprotection •
490 cytokines/chemokines •
699 retinal glia