Although both VEGF and CEP both promote the angiogenesis associated with wet AMD and tumor growth, they do so through orthogonal signaling pathways, i.e., through VEGF and Toll-like receptors, respectively. Therapeutic modalities targeted against the VEGF pathway, i.e., anti-VEGF antibodies or VEGF receptor inhibitors, have proven clinically beneficial for the treatment of wet AMD and cancer. Similar approaches targeted at the CEP pathway, i.e., anti-CEP antibodies or Toll-like receptor inhibitors, seem likely to have clinical utility. Because blocking one of these pathways may lead to compensation by the other, combination therapies may be most effective for inhibiting pathological angiogenesis as well as for achieving optimal control of the precarious balance between the pathological and physiological roles of these signaling pathways since angiogenesis can either promote host defense and tissue repair or exacerbate organ dysfunction resulting in disease. Furthermore, CEP derivatives may have clinical utility for promoting wound healing through TLR2-mediated angiogenesis.
Besides the obvious therapeutic potential of inhibiting CEP-induced angiogenesis for preventing tumor growth or the choroidal neovascularization of “wet” AMD, anti-CEP antibodies and TLR2 inhibitors may have utility for treatment of other oxidation-driven pathologies such as atherosclerosis, in which arterial thickening can depend on its microvasculature. Notably, TLR2 knockout mice are protected from atherosclerosis68
and expression of TLR2 is markedly enhanced in human atherosclerotic plaques.69
It is tempting to speculate that TLR2-mediated activation of innate immunity promotes the deposition of C3d in AMD retinas. TLR2-mediated activation of adaptive immunity70
by CEP may also contribute to the pathogenesis of “dry” AMD.
Two threads of our chemistry hypothesis-driven research on CEPs converge on neuronal pathology. First, as noted at the outset, our basic research on protein modification by HNE led to the discovery that it forms covalent adducts in vivo
that incorporate the ε-amino group of protein lysyl residues in pentylpyrrole modifications (PP-protein in ), and we found that PPs accumulate in neurons in the brain of individuals with Alzheimer’s disease.1
Because of their structural similarities and mechanisms of formation (see ), the co-production of CEPs with PPs is highly likely. Furthermore, we detected CEPs in brain from autistic individuals.33
In the second place, TLR2 expression is increased in cerebral cortical neurons in response to ischemia/reperfusion injury71
that coincidentally involves oxidative damage of lipids and proteins. The amount of brain damage and neurological deficits caused by a stroke are significantly less in mice deficient in TLR2 compared with wild-type control mice. Furthermore, TLR2 is expressed on microglial cells72
, and activation of microglial cell TLR2 by a clinically relevant bacterium, Group B Streptococcus
, causes the generation of NO that induces neuronal death in neonatal meningitis.73
TLR2 also mediates signaling in microglial response to putative “endogenous ligand(s)” generated consequent to axonal injury.74
In an in vitro model in hippocampal slices, ischemia upregulates the expression of TLR2 that then promotes neuronal cell death by fostering the excessive generation of the pro-inflammatory cytokine interleukin-1β.75
Since CEPs are also TLR2 ligands, it seems reasonable to anticipate that CEPs, generated under conditions of oxidative stress, contribute to brain injury, e.g., through activation of microglial TLR2.