Neuroinflammation and Its Resolution: From Molecular Mechanisms to Therapeutic Perspectives

Neuroinflammation, the complex immune response of the central nervous system (CNS), when sustained, is a common denominator in the etiology and course of all major neurological diseases, including neurodevelopmental, neurodegenerative, and psychiatric disorders (e.g., Alzheimer's disease, AD; Parkinson's disease, PD; multiple sclerosis, MS; motor neuron disease; depression; autism spectrum disorder; and schizophrenia). Cellular (microglia and mast cells, two brain-resident immune cells, together with astrocytes) and molecular immune components (e.g., cytokines, complement and patternrecognition receptors) act as key regulators of neuroinflammation (Skaper et al., 2012). In response to pathological triggers or neuronal damage, immune cells start an innate immune response with the aim to eliminate the initial cause of injury. However, when the cellular activity becomes dysregulated, it results in an inappropriate immune response that can be injurious and affect CNS functions. Thus, limiting neuroinflammation and microglia activity represents a potential strategy to alleviate neuroinflammationrelated diseases. The Research Topic collects 20 manuscripts, divided into five sections, that include both original research articles and reviews of the emerging literature and explore the role of neuroinflammation in various neurological diseases. There is particular attention dedicated to the relevant research exploring the mechanisms and mediators involved in the resolution of neuroinflammation. Our aim was to generate a valuable discussion contributing to identify new therapeutic targets in brain damage and providing new drug development opportunities for the prevention and treatment of CNS diseases involving neuroinflammation

An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system ("neuroinflammation"), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell-cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenousmechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation

P2X7 Receptors as a Transducer in the Co-Occurrence of Neurological/Psychiatric and Cardiovascular Disorders: A Hypothesis

Background. Over-stimulation of the purinergic P2X7 receptor may bring about cellular dysfunction and injury in settings of neurodegeneration, chronic inflammation, as well as in psychiatric and cardiovascular diseases. Here we speculate how P2X7 receptor over-activation may lead to the co-occurrence of neurological and psychiatric disorders with cardiovascular disorders. Presentation. We hypothesize that proinflammatory cytokines, in particular interleukin-1β, are key players in the pathophysiology of neurological, psychiatric, and cardiovascular diseases. Critically, this premise is based on a role for the P2X7 receptor in triggering a rise in these cytokines. Given the broad distribution of P2X7 receptors in nervous, immune, and vascular tissue cells, this receptor is proposed as central in linking the nervous, immune, and cardiovascular systems. Testing. Investigate, retrospectively, whether a bidirectional link can be established between illnesses with a proinflammatory component (e.g., inflammatory and chronic neuropathic pain) and cardiovascular disease, for example, hypertension, and whether patients treated with anti-inflammatory drugs have a lower incidence of disease complications. Positive outcome would indicate a prospective study to evaluate therapeutic efficacy of P2X7 receptor antagonists. Implications. It should be stressed that sufficient direct evidence does not exist at present supporting our hypothesis. However, a positive outcome would encourage the further development of P2X7 receptor antagonists and their application to limit the co-occurrence of neurological, psychiatric, and cardiovascular disorders

P2X7 Receptors in Neurological and Cardiovascular Disorders

P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2X7, have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in a channel pore permeable to molecules as large as 900 daltons. The P2X7 receptor was originally described in cells of hematopoietic origin, and mediates the influx of Ca2+ and Na+ and Ca2+ and Na+ ions as well as the release of proinflammatory cytokines. P2X7 receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1β, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7 receptors provides an inflammatory stimulus, and P2X7 receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X7 receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. Apoptotic cell death occurs in a number of vascular diseases, including atherosclerosis, restenosis, and hypertension, and may be linked to the release of ATP from endothelial cells, P2X7 receptor activation, proinflammatory cytokine production, and endothelial cell apoptosis. In this context, the P2X7 receptor may be viewed as a gateway of communication between the nervous, immune, and cardiovascular systems

Methods in Molecular Biology

Primary neuronal cell culture preparations are widely used to investigate synaptic functions. This chapter describes a detailed protocol for the preparation of a neuronal cell culture in which giant calyx-type synaptic terminals are formed. This chapter also presents detailed protocols for utilizing the main technical advantages provided by such a preparation, namely, labeling and imaging of synaptic organelles and electrophysiological recordings directly from presynaptic terminals

Serum amyloid A primes microglia for ATP-dependent interleukin-1\u3b2 release

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1\u3b2 (IL-1\u3b2), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1\u3b2 release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Differing effects of NT-3 and GDNF on dissociated enteric ganglion cells exposed to hydrogen peroxide in vitro

Oxidative stress is widely recognized to contribute to neuronal death during various pathological conditions and aging. In the enteric nervous system (ENS), reactive oxygen species have been implicated in the mechanism of age-associated neuronal loss. The neurotrophic factors neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) are important in the development of enteric neurons and continue to be expressed in the gut throughout life. It has therefore been suggested that they may have a neuoprotective role in the ENS. We investigated the potential of NT-3 and GDNF to prevent death of enteric ganglion cells in dissociated cell culture after exposure to hydrogen peroxide (H2O2). H2O2 treatment resulted in a dose-dependent death of enteric neurons and glial cells, as demonstrated by MTS assay, Bis benzimide and propidium iodide staining and immunolabelling. Cultures treated with NT-3 prior to exposure showed reduced cell death compared to untreated control or GDNF-treated cultures. GDNF treatment did not affect neuronal survival in H2O2-treated cultures. These results suggest that NT-3 is able to enhance the survival of enteric ganglion cells exposed to oxidative stress

Synthesis, reactivity, structures, and dynamic properties of gyroscope like iron complexes with dibridgehead diphosphine cages: pre- vs. post-metathesis substitutions as routes to adducts with neutral dipolar Fe(CO)(NO)(X) rotors

Three routes are explored to the title halide/cyanide complexes trans-Fe(CO)(NO)(X)(P((CH2)14)3P) (9c-X; X = Cl/Br/I/CN), the Fe(CO)(NO)(X) moieties of which can rotate within the diphosphine cages (ΔH‡/ΔS‡ (kcal mol−1/eu−1) 5.9/−20.4 and 7.4/−23.9 for 9c-Cl and 9c-I from variable temperature 13C NMR spectra). First, reactions of the known cationic complex trans-[Fe(CO)2(NO)(P((CH2)14)3P)]+ BF4− and Bu4N+ X− give 9c-Cl/-Br/-I/-CN (75–83%). Second, reactions of the acyclic complexes trans-Fe(CO)(NO)(X)(P((CH2)mCH[double bond, length as m-dash]CH2)3)2 and Grubbs’ catalyst afford the tris(cycloalkenes) trans-Fe(CO)(NO)(X)(P((CH2)mCH[double bond, length as m-dash]CH(CH2)m)3P) (m/X = 6/Cl,Br,I,CN, 7/Cl,Br, 8/Cl,Br) as mixtures of Z/E isomers (24–41%). Third, similar reactions of trans-[Fe(CO)2(NO)(P((CH2)mCH[double bond, length as m-dash]CH2)3)2]+ BF4− and Grubbs’ catalyst afford crude trans-[Fe(CO)2(NO)P((CH2)mCH[double bond, length as m-dash]CH(CH2)m)3P)]+ BF4− (m = 6, 8). However, the C[double bond, length as m-dash]C hydrogenations required to consummate routes 2 and 3 are problematic. Crystal structures of 9c-Cl/-Br/-CN are determined. Although the CO/NO/X ligands are disordered, the void space within the diphosphine cages is analyzed in terms of horizontal and vertical constraints upon Fe(CO)(NO)(X) rotation and the NMR data. The molecules pack in identical motifs with parallel P–Fe–P axes, and without intermolecular impediments to rotation in the solid state

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-\u3b1 and lipopolysaccaride (LPS). TNF-\u3b1 time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-\u3b1 and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-\u3b1 or LPS challenge, being higher in microglia with TNF-\u3b1 and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-\u3b1 treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS