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Page 100 Jayanti et al. Neuroimmunol Neuroinflammation 2020;7:92-108 I http://dx.doi.org/10.20517/2347-8659.2019.14

in MS by modulating IL17 producing T-helper (Th17) cells, and regulatory T cells [72-74] , as well as B cells,
macrophages and dendritic cells. In macrophages, AhR regulates IL1β production and also IL6, IL12 and
[76]
TNFa expression [73,75] . AhR also inhibits the transcriptional activity of NFκB in stimulated macrophages .
Meanwhile, in dendritic cells, AhR mediates the generation of T regulatory cells and Th17 cells from naive
[77]
T cells and also IL10 production . Notably, the injection of low doses of UCB (20 µg/kg body weight,
injected into C57Bl/6 mice) increased the population of regulatory T cells by more than 50% compared
[78]
to controls, prolonging graft survival . Regulatory T cells are also inducible by HO-1 activity, CO, and
[78]
UCB and all “yellow players” [Figure 2].
Optic neuritis and neuromyelitis optica
Reduced TSB has been noticed in both optic neuritis, an acute inflammatory demyelinating disorder of the
optic nerve, and neuromyelitis optica, also known as Devic disease, a severe autoimmune demyelinating
disease that selectively affects the optic nerve and spinal cord [79-82] . Although the main focus was on the
potential antioxidant role of bilirubin, suggesting that the low TSB is a result of the overconsumption of
[83]
bilirubin due to oxidative stress, immunohistochemistry of damaged nerves is similar as in MS , with an
evident inflammatory component. Thus, the interplay between bilirubin and inflammation described in MS
also applies to optic neuritis and neuromyelitis optica. Further studies are needed.

Diabetic retinopathy and stroke
TSB levels have been found to be decreased also in patients with diabetes mellitus and diabetic retinopathy
vs. subjects with diabetes mellitus without retinopathy, suggesting TSB as a biomarker of diabetic
[84]
retinopathy . In the pathogenesis of diabetic retinopathy, particularly in the non-proliferative type,
[85]
hyperglycemia exposure causes the alteration of retinal microvasculature with pericyte loss , endothelial
apoptosis and endothelial thickening of the basement membrane, which further lead to capillary occlusion
[86]
and ischemia .
Similarly, damage and even destruction of the cerebral vasculature are landmarks of stroke and related
[87]
vascular events . In a large study conducted by Li et al. , 343 subjects with silent cerebral infarct
[88]
presented with lower TSB levels. In another study, patients with deep white matter lesions (DWMLs) had a
decreased TSB level compared to non-DWMLs subjects. Again, the low and intermediate bilirubin groups
[89]
showed a higher prevalence of severe DWMLs than did the group with higher bilirubin levels . Notably,
DWMLs are a recognized predictor for the development of impaired cognitive function and stroke [90,91] .

A recent study also explored the association of UCB and intracranial atherosclerosis, which was found in
approximately 50% of patients with transient ischemic attack and up to 47% of ischemic stroke patients in
Asia [92-94] . In this study, UCB was significantly negatively associated with intracranial atherosclerosis. The
odds of intracranial atherosclerosis was 0 0.67-fold lower in participants in the high UCB concentration
group (≥ 10.10 mMol/L) when compared with those in the low UCB concentration group . An increased
[94]
bilirubin level has been proposed as a novel independent predictor for hemorrhagic transformation and
[95]
symptomatic intracranial hemorrhage after mechanical thrombectomy .

The role of bilirubin in all previously mentioned conditions might be explained by a large number of
studies suggesting bilirubin as a protector against microvascular complications. Bilirubin exhibits potent
antiinflammatory effects [via HO-1, nuclear factor erythroid 2-related factor 2 (Nrf2) and NFκB] by the
inhibition of monocyte transmigration [through a decrease in TNFa-induced monocyte chemoattractant
protein-1 (MCP-1) secretion], reducing endothelial vascular cell adhesion molecule-1 (VCAM-1)
expression, and improving endothelial cell dysfunction and hyperproliferation after damage [96-99] . UCB also
appears to affect the immune system by inhibiting the activation of the complement cascade [100] , and also by
modulating the phagocytic and antigen-presenting function of macrophages (by changing the expression of
Fc receptors) [101] .