Potential Association between Methylmercury Neurotoxicity and Inflammation

Abstract

Methylmercury (MeHg) is the causal substrate of Minamata disease and a major environmental toxicant. MeHg is widely distributed, mainly in the ocean, meaning its bioaccumulation in seafood is a considerable problem for human health. MeHg has been intensively investigated and is known to induce inflammatory responses and neurodegeneration. However, the relationship between MeHg-induced inflammatory responses and neurodegeneration is not understood. In the present review, we first describe recent findings showing an association between inflammatory responses and certain MeHg-unrelated neurological diseases caused by neurodegeneration. In addition, cell-specific MeHg-induced inflammatory responses are summarized for the central nervous system including those of microglia, astrocytes, and neurons. We also describe MeHg-induced inflammatory responses in peripheral cells and tissue, such as macrophages and blood. These findings provide a concept of the relationship between MeHg-induced inflammatory responses and neurodegeneration, as well as direction for future research of MeHg-induced neurotoxicity.

1. INTRODUCTION

Methylmercury (MeHg), a well-known pollutant that causes Minamata disease, produces severe neuropathological alterations in parts of the adult cerebral cortex, cerebellum, and dorsal root ganglia (DRG).^1–3) In addition to neurotoxic effects for adults, developmental neurotoxicity of MeHg is an important issue because it is related to both Minamata disease and the existence of MeHg in the environment, especially in seafood.^4–6) Over the past 60 years, numerous studies have suggested mechanisms of MeHg-induced neurotoxicity (as previously reviewed by others).^7–12) However, because it can affect several parallel pathways to elicit overall neurotoxicity, potential mechanisms of MeHg-induced neurotoxicity remain an important target for many neurotoxicologists.

Recently, several studies have suggested neuroinflammation as a possible candidate for MeHg-induced neurotoxicity. In this manuscript, we review recent progress in understanding how MeHg-induced neurotoxicity is related to inflammatory responses.

2. NEURODEGENERATION CAUSED BY NEUROINFLAMMATION AND ITS MECHANISM

The relationship between inflammation and neurodegeneration has been widely studied and is a potential target for clinical therapies. For example, Alzheimer’s disease is a progressive neurodegenerative disease that results in conspicuous neurodegeneration, mainly in the cortex and hippocampus. Although the principal etiology is thought to be an accumulation of amyloid β peptides and neurofibrillary tangles, recent evidence suggests that neuroinflammation is also a potential candidate for neurodegeneration.^13–15) Parkinson’s disease occurs because of neurodegeneration of dopaminergic neurons in the substantia nigra, but several studies imply the possible involvement of neuroinflammation.^14,16,17) Amyotrophic lateral sclerosis (ALS) is characterized by progressive and selective degeneration of motor-associated neurons, and may also involve a causal relationship between neurodegeneration and neuroinflammation.^18–20) Other neurological and psychiatric diseases are reportedly caused by inflammation-associated neurodegeneration, such as frontotemporal dementia,^18–20) depression,²¹⁾ and postpartum depression.²²⁾ In addition, a relationship between infection-induced inflammation and neurodegeneration,²³⁾ as well as ischemia-associated inflammation and neurodegeneration,²⁴⁾ has also been reported. Despite these many reports, anti-inflammatory drugs appear to be less effective and produce more severe side effects, at least as a treatment for Alzheimer’s disease.²⁵⁾ Therefore, further research on the relationship between inflammation and neurodegeneration is highly desired.

Mechanisms of neurodegeneration elicited by direct exposure of neurons to inflammatory cytokines involve several forms of cell death (e.g., necrosis, apoptosis, pyroptosis, and necroptosis) that are activated by pathways such as the production of reactive oxygen species (ROS) or nitric oxygen (NO), mitochondrial disfunction, collapse of calcium homeostasis, inflammasome activation, and/or decreased production and secretion of trophic factors.^26–31) In addition to these mechanisms, high-dose inflammatory cytokines secreted into the brain tissue provoke or aggravate neurodegeneration via microglial/astrocytic failure of calcium homeostasis; production of ROS, NO, and/or peroxynitrite; excess secretion of matrix metalloproteases and glutamate; reduction of phagocytic capacity by decline of phagosome maturation and lysosomes; and decreased neurotrophic factor secretion.^23,32–34) Furthermore, inflammatory responses and secretion of inflammatory cytokines can affect the blood–brain barrier (BBB) and destroy its function, which induces and aggravates neurodegeneration.^35–37) Many studies suggest that inflammation induces neurodegeneration directly and/or indirectly by these mechanisms. Therefore, in the next section, we introduce reports showing MeHg-induced inflammatory responses and discuss their potential association with MeHg-induced neurodegeneration.

3. MICROGLIA

3.1. Basic Properties and Activation of Microglia

Microglia are an immune/inflammation-responsive cell type that exists in the central and peripheral nervous systems.³⁸⁾ Their principal physiological role is thought to be maintaining homeostasis of the nervous system, which is achieved by phagocytosis of cell debris, unnecessary neuronal structures (including synapses), and infectious agents.³⁹⁾ Under normal conditions, microglia expand several protrusions in all directions to monitor their local environment.⁴⁰⁾ In addition, they interact with surrounding neurons and glia by secreting several physiologically active factors.^39,41) When microglia perceive environmental changes, such as exposure to toxicants, ischemia, or infection of viruses, they quickly respond by changing morphologically, proliferating, infiltrating into the damaged area, phagocytosing dead cells, and/or secreting several pro- and anti-inflammatory cytokines and trophic factors.⁴²⁾ Classically, microglia are activated into one of two different states: M1-type pro-inflammatory microglia or M2-type anti-inflammatory microglia.⁴²⁾ M1 microglia function to phagocytose damaged cells and cell debris, and secrete pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. In contrast, M2 microglia elicit tissue repair and wound healing by secreting IL-10 and transforming growth factor β. In addition to these functions, microglia have recently been suggested to regulate neurogenesis and synaptic plasticity, which are associated with learning and memory.^43,44)

Notably, although many reports describe how MeHg-induced microglial dynamics affect neurotoxicity, the results are not necessarily consistent because of different experimental conditions. Regardless, these results provide important knowledge to understand the mechanism of MeHg-induced neurotoxicity.

3.2. Methylmercury-Induced Cell Death and Proliferation of Microglia

The effect of MeHg on microglial cell death has been demonstrated in several reports, which suggest that the LD₅₀ for microglia (3–12 µM)^45–48) is relatively high compared with neurons (0.5–3 µM).^49–51) Moreover, exposure to low-dose MeHg reportedly enhances microglial proliferation.⁵²⁾ Microglia change their morphology in response to exposure to numerous stimuli. In experiments using MeHg-exposed primary cultures, brain slice cultures, and animal models, microglia changed their shape into a sphere-like form (often called amoeboid-shape microglia) with a small number of thin protrusions.^53–57) In addition, microglial proliferation in MeHg-exposed animal models has been observed. For example, an increased number of microglia were observed in the cerebellar cortex,⁵⁸⁾ cerebellum,⁵⁷⁾ hippocampus,⁵⁶⁾ and DRG^59,60) of rodents, as well as the occipital lobe of common marmoset.⁶¹⁾ Furthermore, proliferating reactive microglia were observed in the visual cortex of macaque monkeys exposed to MeHg for 1 year.⁶²⁾

Microglia may elicit responses to lower doses of MeHg compared with other cells, which may support their protective effect on neurons and other cells.^{47,48,53,63,64)} The many studies showing that MeHg exposure changes the state of microglia and increases their number suggest that qualitative and quantitative alterations of microglia can positively and/or negatively affect neurodegeneration.

3.3. Methylmercury-Induced Release of Proinflammatory Cytokines from Microglia

The release of proinflammatory cytokines from microglia following MeHg exposure has also been investigated. Expression and secretion of one of the most well-studied pro-inflammatory cytokines, IL-6, is increased following MeHg exposure in both cultured cells and animal models.^46,65,66) In contrast, some studies have shown decreased^53,67) or unchanged⁶⁸⁾ expression and secretion of IL-6. The differences between these results may arise from differences in experimental conditions; however, the details are unknown. Other cytokines, such as TNF-α^52,54,66,69) and IL-1β,^52,66) are also increased following MeHg exposure, as revealed by mRNA and protein assays. However, reduced expression of TNF-α mRNA following low-dose MeHg exposure⁵²⁾ and no change of TNF-α following MeHg exposure⁵³⁾ have also been reported. Increased expression of TNF-α was observed in MeHg-exposed mouse cerebellar cortex and cerebellum,⁷⁰⁾ and the origin of TNF-α was reported as microglia.⁶⁹⁾

4. ASTROCYTES

Astrocytes, the most populous cells in the central nervous system (CNS), display high heterogeneity⁷¹⁾ and perform numerous functions such as: physical support of neuronal networks including formation of the BBB⁷²⁾; secretion of trophic factors, neurotransmitters, and hormones⁷³⁾; quick clearance of neurotransmitters from the extracellular region to maintain homeostasis of neurotransmission⁷⁴⁾; and association of synaptic plasticity to affect learning and memory.⁷⁵⁾ Astrocytes, as well as microglia, have a relatively high LD₅₀ (>5 µM) for MeHg compared with neurons.^76,77) MeHg-exposed human astrocytes change their activated morphology and induce immune responses.^78,79) MeHg enhanced secretion of TNF-α⁷⁶⁾ and expression of IL-6⁸⁰⁾ and C-C motif chemokine ligand 2 (CCL2)⁸¹⁾ in astrocytes, suggesting that astrocytes can act in both a neurodegenerative and neuroprotective manner⁸²⁾ in addition to microglia and macrophages. In addition, expression and secretion of S100B are enhanced in MeHg-exposed astrocytes.⁸³⁾ The secreted protein S100B elicits a neuroprotective effect at low levels, but can cause neuronal injury at high levels induced by inflammation responses.⁸⁴⁾ In an animal model, MeHg exposure also increased expression of both S100B mRNA and protein.⁸⁵⁾ Cell-to-cell interactions between astrocytes and microglia also reportedly enhanced MeHg-induced IL-6 secretion from microglia.⁵³⁾

5. NEURONS

The LD₅₀ of MeHg on neurons was previously reported to be in the range of 0.5–3 µM.^49–51) Although neurons are not major inflammatory responsive cells, cytokines derived from neurons can affect surrounding cells and/or even the neuron itself in para- and autocrine mechanisms, respectively. Primary cultures of neurons always contain several types of cells, including glia; thus, evidence of MeHg directly altering cytokine expression and/or secretion from neurons has still not been achieved. However, previous reports using neural cell lines and neural stem cell lines suggest MeHg may directly regulate cytokine expression in neurons. For example, enhancement of IL-1β, IL-6, TNF-α, and interferon γ, and reduced IL-10 expression were observed in the human neuroblastoma cell SH-SY5Y following MeHg exposure.⁸⁶⁾ In addition, MeHg exposure upregulated TNF-α in the mouse neural stem-like cell line C17.2.⁷⁰⁾ The same group also demonstrated that the increase of C-C motif chemokine ligands CCL3 and CCL4 induced by MeHg may potentially contribute to neuroprotection.^87,88)

6. MACROPHAGES

Macrophages are a type of white blood cell associated with the immune system and inflammatory responses.⁸⁹⁾ The majority of macrophages are peripherally differentiated from circulating monocytes, which penetrate from the blood through blood vessels into injured organs upon detection of an infringement of the biological environment, such as trauma, inflammation, or invasion of pathogens. The other macrophages are called tissue-resident macrophages (derived from circulating blood monocytes during early development) and are distributed in each organ, whereby they fulfill tissue-specific functions.⁹⁰⁾ Differentiated macrophages engulf damaged cells and invaded pathogens to contribute to biological homeostasis. Macrophages express many common genes with microglia; accordingly, macrophages (monocytes) were long thought to be the source of microglia-like tissue-resident macrophages, however this has recently been challenged.⁹¹⁾ Although macrophages and microglia arise from different cell lineages, they are frequently introduced in a similar context for responses against external factors. Importantly, both show similar activated forms (i.e., M1 and M2 subtypes), have phagocytic functions and cell protective effects, and secrete similar cytokines.

Infiltrated macrophages are observed in the CNS of patients with Minamata disease.⁹²⁾ In addition, some studies have investigated the effect of MeHg on macrophages. Although the results depend on the experimental conditions, in vitro experiments demonstrate that the LD₅₀ of MeHg exposure for cultured macrophages is relatively high (3–20 µM) compared with neurons.^93–96) In animal models of infection and obesity, MeHg induced cardiac accumulation of macrophages⁹⁷⁾ and increased numbers of cell-protective M2-type CD204-positive macrophages in the brain, kidney, and spleen.⁹⁸⁾ The effect of MeHg on expression of cytokines by macrophages has also been investigated. Expression levels of MIP-2 (the mouse homologue of human IL-8) and MCP-5 (the mouse homologue of human MCP-1) are enhanced in mouse macrophages following MeHg exposure.⁹⁴⁾ MeHg also induced expression of IL-6 and IL-8 in human macrophages.⁹⁵⁾

Interestingly, some reports show that macrophages potentially function to accumulate organic mercury compounds and convert them into inorganic mercury using their strong phagocytic functions. For example, mercury was accumulated in regions containing fish melanomacrophages⁹⁹⁾ and macrophages of MeHg-exposed rat DRG.¹⁰⁰⁾ Moreover, macrophages can convert organic mercury compounds into inorganic mercury.¹⁰¹⁾ Taken together, this reported activation and aggregation of macrophages indicate a potential role in mercury detoxication.

7. EFFECTS OF CYTOKINES IN THE BLOOD

Many reports suggest that cytokines in the blood can penetrate the BBB. Indeed, saturable transport systems from blood to the CNS have been well documented for IL-1α, IL-1β, IL-6, and TNF-α.¹⁰²⁾ The components of blood and blood vessels show upregulation of cytokine expression and secretion. For example, as described above for macrophages, expression and secretion of cytokines from MeHg-exposed lymphocytes,¹⁰³⁾ monocytes,¹⁰⁴⁾ and vascular endothelial cells¹⁰⁵⁾ have been reported. Thus, cytokines derived from other organs following induction by MeHg should also be considered. Increased expression of cytokines or chemokines following MeHg exposure has been reported in several organs including the kidney, liver, and spleen.^106,107) These cytokines derived from certain organs and blood cells following MeHg exposure may affect CNS neurons by penetrating the BBB. Indeed, a cohort study showed a positive correlation between blood MeHg and the blood cytokine ratio of T-helper1 (cell-mediated immunity) to T-helper2 (humoral immunity).¹⁰⁸⁾ In contrast, cytokine levels in cord blood were unaffected by MeHg exposure of the mother.¹⁰⁹⁾ Therefore, the effect of MeHg on cytokine levels may need to be considered separately for adult and fetus.

8. CONCLUSION

In the present review, we overviewed the relationship between MeHg-induced inflammation and neurodegeneration, including mechanisms of neurodegeneration caused by inflammation, MeHg-responsive cells in the CNS (e.g., microglia, astrocytes, and neurons), MeHg-responsive cells in blood (i.e., macrophages), and cytokines derived from blood. We did not show evidence that MeHg-elicited inflammatory responses directly induce neurodegeneration or neuroprotection; however, many data referred to in this manuscript suggest the possibility that inflammation directly affects MeHg-induced neurodegeneration. Inflammatory responses including activation of microglia and macrophages have physiological functions in both neural injury and neuroprotection. Therefore, further investigations are required to understand the detailed relationship between MeHg-induced inflammatory responses and neurodegeneration.

Acknowledgments

We would like to thank professor Dr. G-W. Hwang for helpful comments and advice. We are also thankful for funding from the Study (Group) of the Health Effects of Heavy Metals Organized by the Ministry of the Environment, Japan; and Grants-in-Aid for KAKENHI from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [22K11403].

Conflict of Interest

The authors declare no conflict of interest.

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