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Jayanti et al. Neuroimmunol Neuroinflammation 2020;7:92-108 I http://dx.doi.org/10.20517/2347-8659.2019.14 Page 99

Figure 3. Multiple ways of bilirubin as immunomodulator in neuroinflammation disease. Ahr: aryl hydrocarbron receptor; APC: antigen
presenting cell; BDNF: brain-derived neurotrophic factor; DC: dendritic cell; FcR: Fc receptor; GDNF: glial cell line-derived neurotrophic
factor; IFNγ: Interferon γ; IL: interleukin; MHC II: major histocompatibility complex; PI3K/Akt: phosphatidylinositol 3-kinase; Th: T helper;
TCR: T cell receptor

Histological analyses demonstrated that bilirubin interfered with the infiltration of inflammatory cells
[64]
into the CNS by protecting the blood-brain barrier from free radical-induced permeability changes ,
stressing the intimal connection between redox stress and inflammation in CNS diseases. Further study
[64]
supported the antiinflammatory potential of bilirubin in the EAE model . In vitro experiments using
+
spleen-harvested CD4 T cells showed that bilirubin at non-apoptotic concentrations (20-150 mM)
+
inhibits CD4 T cell proliferation through various mechanisms. It suppresses the production of T helper-1
(Th1) cytokines (IL2 and IFNγ) and Th2 cytokines (IL4 and IL10), reduces costimulatory molecule
+
activity (CD28 on CD4 T cell, the co-receptor B7-1 activity in macrophages and dendritic cells), inhibits
NFkB activation, which is a key transcription factor involved in T cell receptor-mediated signaling, and
downregulates inducible MHC (major histocompatibility complex) class II expression. Bilirubin effectively
+
downregulates EAE in SJL/J mice as confirmed by the reduction of the proliferation capacity of CD4 T cell.
Meanwhile, the reduction of endogenous bilirubin synthesis by zinc-protoporphyrin, a specific inhibitor of
[66]
the bilirubin producing-enzyme HO-1, dramatically exacerbates this disease . In contrast, induction of
HO-1 by cobalt protoporphyrin IX (CoPPIX) inhibits EAE effectively .
[67]
According to the previous data, it seems beneficial to increase bilirubin synthesis through HO-1
induction. Several clinically used drugs have been reported to induce HO-1, among them are nonsteroidal
antiinflammatory drugs (e.g., coxibs, acetylsalicylic acid) and hypolipidemic agents (e.g., niacin, fibrates,
[68]
statins) . Atorvastatin and rosuvastatin treatment in mice demonstrated protection by increasing not
only plasma bilirubin concentrations (up to 70%) but also cardiac tissue bilirubin content (up to 119%) .
[69]
On the contrary, HO-1 induction in astroglia promotes oxidative mitochondrial membrane damage, iron
sequestration, and mitophagy (macroautophagy) . These reasons then increase the doubt of bilirubin
[56]
synthesis through HO-1 induction as a good strategy to counteract the neuroinflammatory process.

In another part of inflammation signalling pathways, both UCB and biliverdin are known as activators of
aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that plays critical modulatory
roles in various immune cells during innate and adaptive immune responses [2,70,71] . AhR has critical roles