Recent studies have implicated local TNF-α in POAG etiology: TNF-α is generated by retinal glia in response to hypoxia and elevated pressure; the retina and optic nerve TNF-α and TNF-R1 expression is elevated in glaucomatous eyes; and TNF-α injection causes retinal ganglion cell (RGC) apoptosis and optic nerve degeneration.
37–41 However, the protective associations with higher circulating sTNF-R2 and TNF-α are also biologically plausible. For example, in the central nervous system, TNF-α induces protective prosurvival signals mediated by various TNF receptors, such as TNF-R2,
42–44 as well as downstream factors such as NF-κB (involved in the expression of genes related to neuronal survival)
45 and TANK-binding kinase 1 (interestingly, a rare genetic variation in this enzyme was associated with NTG).
46 Another possible mechanism is that systemic TNF-α levels, associated with higher blood pressure,
47 may be associated with greater ocular perfusion pressure, which may improve the blood flow and survival of the optic nerve,
48,49 especially in women who generally have lower blood pressure (and consequently, lower ocular perfusion pressure). Alternatively, TNF-α induces adipocytes to secrete the appetite-suppressing hormone leptin,
50–53 and recent studies have revealed that leptin is neuroprotective
54 and provides strong neuronal survival signals by inhibiting apoptosis.
55,56 Interestingly, the association between TNF-α and leptin is known to be stronger in females
57,58 and TNF-α levels are generally higher in women than in men (as has also been shown in this study)
59 ; indeed, in preliminary analyses of leptin levels and POAG risk (unpublished data), we observed a 58% reduced risk of POAG (relative risk [RR] = 0.42 [95% CI = 0.18–0.95]) comparing the highest with lowest tertile in women and a nonsignificant association in men. Fourth, a similar finding of low cerebrospinal fluid levels of TNF-α has been found in patients with normal pressure hydrocephalus (NPH),
60 which has been associated with glaucoma and involves a loss of global neuronal tissue without elevated intracranial pressure.
61,62 Finally, circulating sTNF-R2 may cross into the eye and bind to locally generated TNF-α to block its detrimental effects, as evidenced by systemic treatment with etanercept (Enbrel; Amgen, Thousand Oaks, CA), which contains TNF-R2, being able to rescue RGCs exposed to TNF-α generated with ocular hypertension in an experimental rat model.
63 Thus, the observed associations with sTNF-R2 clearly have some biologic plausibility and warrant further study.