首都医科大学三博脑科医院癫痫中心 李天富 高青 栾国明

Abstract

Rasmussen’s encephalitis is neurological disorder of childhood characterized by unihemispheric inflammation, intractable focal epilepsy and progressive cognitive and neurological deficits. Currently, the pathogenesis of Rasmussen’s encephalitis is still enigmatic and hemispherectomy is the only effective method to control the seizures associated with Rasmussen’s encephalitis. Recently data indicated that intrinsic activation of endogenous pro-inflammation high-mobility group box-1 (HMGB1) and Toll-like receptor (TLR) is involved in the development of Rasmussen’s encephalitis. Activation of HMGB1-TLR signaling plays a critical role in brain inflammation,development of epilepsy and cognitive dysfunction. Targeted therapy on HMGB1-TLR signaling might be a novel strategy with antiinflammtion,anti-epilepsy as well as improving cognitive dysfunction associated with epilepsy in Rasmussen’s encephalitis.

Key words: Rasmussen’s encephalitis,epilepsy, inflammation, cognition, HMGB1,

Introduction

Rasmussen’s encephalitis is a very rare chronic progressive inflammatory neurological disorder of uncertain etiology affecting mostly children and associated with hemispheric atrophy, focal epilepsy (epilepsia partialis continua),cognitive deterioration and progressive neurological deficits,resulting from progressive loss of function subserved by the involved cerebral hemisphere (Bien et al., 2002; Bien et al., 2005; RASMUSSEN et al., 1958). The aetiology and pathogenesis of Rasmussen’s encephalitis, in particular, the factors responsible for the characteristic of asymmetry are still elusive. Currently, hemispherectomy is the only effective method to control the seizures associated with Rasmussen’s encephalitis. Increasing experimental and clinical evidence supports a link among inflammation, epilepsy (both in terms of epileptogenesis and the long-term consequences of seizures) and cognitive dysfunction associated with epilepsy,which indicates that activation of inflammatory processes in the brain is a common feature of various epileptic disorders(Vezzani et al., 2013). Recently study demonstrates that intrinsic activation of endogenous pro-inflammation highmobility group box-1 (HMGB1) and Toll-like receptor (TLR) are involved in the development of Rasmussen’s encephalitis(Luan et al., 2016). Activation of HMGB1-TLR plays a critical role in brain inflammation, development of epilepsy and cognitive dysfunction, and inhibition of HMGB1-TLR signaling demonstrates anti-inflammtion, anti-epilepsy as well as improving cognitive dysfunction associated with epilepsy (Vezzani et al., 2013).

HMGB1-TLR signal ing and brain inflammation

HMGB1-TLR may represent a novel pro-inflammatoryaxis following sterile brain injury (Walker and Sills, 2012).Activation of proinflammatory cytokines especially HMGB1-TLR signaling involves in immune response to inflammation associated with many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis and epilepsy (Vezzani etal., 2013; Glass et al., 2010), and subserve neuromodulatory functions implicated in brain physiology and may contribute to acute and chronic neurodegeneration. HMGB-1,characterized as a key cytokine (Lotze and Tracey, 2005),is a 216 amino acids (29 kDa) DNA-binding protein with a highly conserved structure in several species (Thomas,2001). HMGB-1 participates in nucleosome formation and regulation of gene transcription (Stros et al., 2002; Park et al., 2003), including proinflammatory genes (Bianchi and Manfredi, 2009). HMGB1 acts as a“danger signal” and alerts the immune system to damaged or dying cells. In response to inflammatory stimuli, HMGB-1 is secreted by activated macrophages (Bonaldi et al., 2003), natural killer cells (Semino et al., 2005), myeloid dendritic cells (Lotze and Tracey, 2005) and astrocytes (Maroso et al., 2010)binding to RAGE and TLR, including TLR2 and TLR4. The hyperacetylated form of HMGB1 regulates transcription of various pro-inflammatory cytokines, including IL-1β,through binding to TLR2, TLR4 and also to RAGE (Maroso et al., 2011; Bianchi and Manfredi, 2009). In human brain cortex, HMGB1 immunoreactivity expressed in nuclei of neurons and glia cells (Zurolo et al., 2011; Luan et al., 2016).When under immune/inflammatory challenges or injuriousconditions, HMGB-1, normally residing in nuclei, translocates to the cytoplasm and/or extracellular space (Bianchi and Manfredi, 2009; Scaffidi et al., 2002). Extracellular HMGB1 acts as a ‘danger signal’ to orchestrate a homeostatic defensive response in challenged tissues; however, under circumstances that remain poorly understood, the resolution of inflammation is compromised, its pro-inflammatory properties, acquired upon its cellular release and consequent TLR/RAGE stimulation, appear to contribute to the pathogenesis of various inflammatory and CNS diseases(Bianchi and Manfredi, 2007).

TLR4 and TLR2 are preferentially expressed on cells that play central roles in innate immune responses, includingmacrophages and microglia, but it is present at very low or undetectable levels on neurons and astrocytes, (Kim et al.,2000; Luan et al., 2016; Zurolo et al., 2011). As the major initial sensors of danger or stranger signals recognized by TLR4, Microglia secrete inflammatory cytokines to induce secondary inflammatory responses by acting on astrocytes(Saijo et al., 2009). Therefore, Microglia plays critical roles in establishing and maintaining inflammatory responses in the context of neurodegenerative diseases (Glass et al.,2010). TLRs play a key role in pathogen recognition, which recognize a diverse set of pathogen-associated molecules that are not present in the host, and culminate in activation of the transcription factor nuclear factor-kappa B, which controls the expression of an array of inflammatory cytokine genes (Kawai and Akira, 2007). In the absence of pathogens, TLR signalling can be activated by molecules released by injured tissue, namely damage-associated molecular patterns, which include HMGB1 (Bianchi and Manfredi, 2009). Activation of TLR2 and TLR4 pathway plays an important role in the pathogenesis of several chronic inflammatory diseases in animal models, contributing to inflammatory programs associated with neurodegenerative disease including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis and epilepsy (Vezzani et al., 2013; Glass et al., 2010).

HMGB1/TLRsignalingandepilepsy

Extensive experimental and clinical evidence supports a link between inflammation and epilepsy, both in terms of epileptogenesis and the long-term consequences of seizures,which indicates that activation of inflammatory processes in the brain is a common feature of various epileptic disorders (Maroso et al., 2011; Vezzani et al., 2013; Vezzani et al.,2011; Vezzani et al., 2011). Therefore, brain inflammation is regarded as a diagnostic, prognostic or therapeutic biomarker for epilepsy (Vezzani and Friedman, 2011). Recent studies demonstrate that activation of HMGB1/TLR signaling pathways plays a crucial role in the development of epilepsy.Activation of HMGB1–TLR signaling has been recently demonstrated in epileptogenic brain tissue from drugresistant epilepsy patients with Rasmussen's encephalitis (Luan et al., 2016), the prototype of inflammatory and immune-mediated epileptic encephalopathy, but also with temporal lobe epilepsy (Maroso et al., 2010) and focal malformations of cortical development (Zurolo et al., 2011) without infectious or immune-mediated etiology. In particular,antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence, which highly suggest that activation of HMGB1–TLR-RAGE pathway possibly represents a common mechanism of epileptogenesis (Ravizza et al., 2011).

Rasmussen's encephalitis is a rare chronic progressive inflammatory neurological disorder with pharmacoresistant focal epilepsy (epilepsia partialis continua) (Takei et al., 2010;Bien et al., 2005; RASMUSSEN et al., 1958). There might be a linking between activation of the innate immune system and consequent inflammation to epilepsy of Rasmussen's encephalitis. The chronic inflammation is—at least partly the consequence of a cycle in which inflammation induced cell injury leads to the release of endogenous dangerassociated molecular pattern that drives the inflammatory response, causing further damage and inherent epileptogenicity of brain lesions, pathogenic or otherwise (Walker and Sills, 2012). The intralesional overexpression and cellular distribution of HMGB1 and its cognate receptorsTLR2, TLR4 and RAGE in specimens from Rasmussen's encephalitis patients with medically intractable epilepsy has been demonstrated (Luan et al., 2016): (i) cytoplasmic translocation of HMGB1 was detected in the neurons,reactive astrocytes and reactive microglial cells within the lesions; (ii) Increases in the immunoreactivity of HMGB1 in reactive astrocytes (predominant in cytoplasm) was observed; (iii) intralesions expression of RAGE, TLR4 and TLR2 was also elevated in both neurons, reactive astrocytes and reactive microglial cells, particularly in reactive astrocytes. Although HMGB1 release and signaling may be a general feature of all epilepsies, expression of HMGB1,TLR2, TLR4 and RAGE was more markedly increased in perivascular areas, and endothelial cells in walls of blood vessels within the lesions cortex displayed immunoreactivity in Rasmussen's encephalitis patients. These findings are concomitant with the reactive astrogliosis, neuron loss and inflammation (i.e. CD8-positive, CD3-positive T lymphocyte).The evidence further supported the role of HMGB1-TLR pathway in activation of immune and endothelial cells in the pathogenesis of Rasmussen's encephalitis (Luan et al.2016).

HMGB1/TLR signaling and cognition

Brain in flamma tion has been implicated in th epathophysiology of several neuropsychiatric conditions.Therefore, inflammatory processes which are triggered in the brain by an epileptogenic insult may, concurrently with seizures, lead to the development of neuropsychiatric abnormalities (Vezzani et al., 2013). As a crucial regulator mediating epilepsy development and brain inflammation,HMGB1/TLR signaling also has been implicated in the pathophysiology of cognitive and psychiatric phenotypes.RAGE mediated inflammatory pathway plays an important negative regulator of learning and memory. In particular,the increased RAGE signaling has been implicated in mechanisms of memory impairments in Alzheimer's disease,and RAGE is regarded as a potential therapeutic target to ameliorate cellular dysfunction and cognitive dysfunction(Arancio et al., 2004). Recent evidence indicated that HMGB1 and its corresponding receptors are upregulated in the inflammation pathway in epileptic tissue and may play a crucial role in the development and perpetuation of seizures and cognitive dysfunction associated with epilepsy (Vezzani et al., 2013; Maroso et al., 2010). To elevate the brain levels of HMGB1 via intracerebroventricular administration has been proven to precipitate seizures and disrupted object memory mediated by either TLR4, or RAGE (Mazarati et al.,2011). Refractory focal seizures and cognitive deterioration are the clinical features of Rasmussen's encephalitis, a rare progressive inflammatory disorder of uncertain etiology (Bien et al., 2005; RASMUSSEN et al., 1958). Upregulation of HMGB1, TLR4 and RAGE in reactive microglia, reactive astrocytes, neurons and vascular endothelial cells has been demonstrated in the brain lesion area of Rasmussen's encephalitis. Therefore, HMGB1-induced overstimulation of RAGE or TLR4 might contribute to memory deficits in Rasmussen's encephalitis.

Acknowledgment

This Project was supported by the Grant from the BIBDPXM2013_014226_07_000084, National Natural Science Foundation of China (81571275), Scientific Research Common Program of Beijing Commission of Education (KM201410025027). We confirm that we have read the

Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Competing interests

The authors declare that they have no competing interests.