Regenerative Effects of Heme Oxygenase Metabolites on Neuroinflammatory Diseases

Abstract

Heme oxygenase (HO) catabolizes heme to produce HO metabolites, such as carbon monoxide (CO) and bilirubin (BR), which have gained recognition as biological signal transduction effectors. The neurovascular unit refers to a highly evolved network among endothelial cells, pericytes, astrocytes, microglia, neurons, and neural stem cells in the central nervous system (CNS). Proper communication and functional circuitry in these diverse cell types is essential for effective CNS homeostasis. Neuroinflammation is associated with the vascular pathogenesis of many CNS disorders. CNS injury elicits responses from activated glia (e.g., astrocytes, oligodendrocytes, and microglia) and from damaged perivascular cells (e.g., pericytes and endothelial cells). Most brain lesions cause extensive proliferation and growth of existing glial cells around the site of injury, leading to reactions causing glial scarring, which may act as a major barrier to neuronal regrowth in the CNS. In addition, damaged perivascular cells lead to the breakdown of the blood-neural barrier, and an increase in immune activation, activated glia, and neuroinflammation. The present review discusses the regenerative role of HO metabolites, such as CO and BR, in various vascular diseases of the CNS such as stroke, traumatic brain injury, diabetic retinopathy, and Alzheimer's disease, and the role of several other signaling molecules.

Keywords: bilirubin; carbon monoxide; heme oxygenase; neuroinflammation; regeneration.

Figure 1

Inflammatory response is mediated by the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), hypoxia-inducible factor (HIF)-1α, and reactive nitrogen species (RNS (e.g., ONOO⁻)) production. This is strongly associated with glia scar formation, pericyte cell death, and invasion of monocytes in the acute phase of various vascular injuries such as stroke, traumatic brain injury (TBI), diabetic retinopathy, and Alzheimer’s disease (AD). Heme oxygenase (HO) metabolites, such as carbon monoxide (CO) and bilirubin (BR) play a role in anti-inflammation and cytoprotection through inhibiting the NF-κB-mediated production of various cytokines. After CO treatment, CO-mediated HO-1 induction in endothelial cells (ECs) may facilitate angiogenesis partly via crosstalk between HO/CO and endothelial nitric oxide synthase (eNOS)/nitric oxide (NO). In addition, the HO metabolites CO and BR may stimulate neurogenesis partly via a Ca²⁺/calmodulin-mediated neuronal NOS (nNOS)/NO pathway in neural stem cells (NSCs).

Figure 2

Possible role of HO metabolites in the retina: (A) HO metabolites may activate cyclic guanosine monophosphate (cGMP)-gated channels in photoreceptors partly via crosstalk between perivascular cells and photoreceptors. In the presence of HO metabolites, cGMP levels in the outer segment membrane may be high; cGMP binds to cation (Na⁺ and Ca²⁺)-permeable channels in the membrane, keeping them open and depolarizing the photoreceptor. (B) The complex architecture of the retina may be strengthened by HO metabolites. A neuronal chain from the photoreceptors to the bipolar cells to the ganglion cells provides the most direct route for transmitting visual information to the brain. Cellular networks comprising various retinal cells (e.g., Müller cells, ECs, pericytes, NSCs, oligodendrocytes, and microglia) can lead to self-repair by regenerating retinal neurons and vessels after retinal injury by HO metabolite-mediated neurotrophic factors. ONL is the outer nuclear layer, INL is the inner nuclear layer, and GCL is the ganglion cell layer.

Figure 3

HO metabolites such as CO, can lead to the secretion of various factors (e.g. BDNF, OPN, SDF-1, and VEGF) associated with the regenerative machinery. These factors can bind to their specific receptors, stimulating signaling axes such as MEK-ERK1/2, and PI3K-Akt in ECs and NSCs, possibly resulting in angiogenesis and neurogenesis.

Figure 4

Possible role of heme oxygenase metabolites in a powerful self-repair mechanism. Carbon monoxide and bilirubin may reduce neuroinflammation and increase the secretion of neurotrophic and growth factors. Released factors can bind to their receptors in neighboring cells, such as endothelial cells and neural stem cells, enhancing cellular interactions. Generation of new vessels and differentiation of NSCs into mature neurons may repair neural circuits in the brain and retina.