Immuno-inflammatory Pathways Research Articles

Commentary: Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy.

Translational research to discover therapeutic targets for stroke has not fared well in developing new treatments for patients. The three most pressing issues are the choice of therapeutic target, animal model, and timepoint of administration of treatment. This manuscript “Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy” provides a fresh approach toward developing stroke treatments (Offner et al., 2014). This study examines treating with recombinant TCR ligand (RTL) in both young and older mice 4 hours after MCAO. RTL consist of the specific domains of MHC II molecule and inhibits activation of T cells toward inflammation. The novelties of this study are several fold including: (1) inhibition of a specific immunoinflammatory pathway to avoid total immunosuppression, (2) use of elderly mice to mimic the population of human patients and (3) administration at a clinically relevant timepoint. For a number of years, researchers have reported the entry of immune cells into the area of the infarct, which leads to further neurodegeneration. However, targeting this immune response as a treatment for stroke remains elusive (Iadecola and Anrather, 2011). In the past several years, the spleen has been reported to be a focal point for the immune system to mount an inflammatory response that exacerbates stroke-induced neurodegeneration (Offner et al., 2006; Vendrame et al., 2006). In fact, ablation of the spleen reduces inflammation and neural cell death in the rodent brain after experimental stroke (Ajmo et al., 2008; Ostrowski et al., 2012; Jin et al., 2013). Blockade of interferon gamma signaling has been reported to be neuroprotective in experimental stroke (Liesz et al., 2009, 2011; Seifert et al., 2014) although other groups have reported alternative results in their model systems (Chu et al., 2000; Lambertsen et al., 2004). T cells are the main effector cell of this neurodegenerative response and responsible for the release of the proinflammatory interferon gamma, which is a potent activator of microglia becoming neurotoxic (Boehm et al., 1997; Mebius and Kraal, 2005). Moreover, addition of interferon gamma reverses the neuroprotection provided by splenectomy, demonstrating that this cytokine plays a major role in the spleen eliciting response resulting in further neural death after stroke (Seifert et al., 2012). As shown in this study, administration of RTL directly inhibits the T cell response to stroke, which concomitantly deactivates the splenic response as well in both young and old mice. This treatment reduced infarct volumes in both age groups by altering the immune response to this neurological insult. Most interestingly, the recombinant TCR ligand differentially affected components of the immune response in the elderly and young mice but still resulted in a blunted immune response reducing neurodegeneration. This study illuminated differences in the immune cell composition and inflammatory expression between these two age groups in response to stroke. This is one of the few studies that enlists elderly animals which begins to provide insight into the differences in the physiological responses to stroke between young and the aged animals. Such differences in young and elderly could be responsible for the failure to translate findings at the bench to those in the clinic since the vast majority of studies use greatly cheaper young ones. More studies using elderly rodents will further supply additional insight in translating stroke treatment from the preclinical research to the clinical setting. This study sets the basis for future ones to develop new therapeutic approaches for a treatment for stroke.

Honokiol abrogates lipopolysaccharide-induced depressive like behavior by impeding neuroinflammation and oxido-nitrosative stress in mice

Depression is an inflammatory, commonly occurring and lethal psychiatric disorder having high lifetime prevalence. Preclinical and clinical studies suggest that activation of immuno-inflammatory and oxido-nitrosative stress pathways play major role in the pathophysiology of depression. Honokiol (HNK) is a biphenolic neolignan possessing multiple biological activities including antioxidant, anti-inflammatory, anxiolytic, antidepressant and neuroprotective. The present study investigated the effect of HNK (2.5 and 5mg/kg, i.p.) pretreatment (30min prior to LPS) on lipopolysaccharide (LPS) (0.83mg/kg, i.p.) induced depressive like behavior, neuroinflammation, and oxido-nitrosative stress in mice. HNK pretreatment at both the doses significantly attenuated LPS induced depressive-like behavior by reducing the immobility time in forced swim and tail suspension test, and by improving the anhedonic behavior observed in sucrose preference test. HNK pretreatment ameliorated LPS induced neuroinflammation by reducing IL-1β, IL-6 and TNF-α level in hippocampus (HC) and prefrontal cortex (PFC). HNK pretreatment prevented LPS evoked oxidative/nitrosative stress via improving reduced glutathione level along with reduction in the lipid peroxidation and nitrite level in HC and PFC. Pretreatment with HNK also prevented the increase in plasma corticosterone (CORT) and decrease in hippocampal BDNF level in LPS challenged mice. In conclusion, current investigation suggested that HNK pretreatment provided protection against LPS-induced depressive like behavior which may be mediated by repression of pro-inflammatory cytokines as well as oxido-nitrosative stress in HC and PFC. Our results strongly speculated that HNK could be a therapeutic approach for the treatment of depression and other pathophysiological conditions which are closely associated with neuroinflammation and oxido-nitrosative stress.

Oxidative/Nitrosative Stress and Immuno-inflammatory Pathways in Depression: Treatment Implications

This paper reviews recent work on the biological underpinnings of clinical depression emphasizing the crucial role of immunoinflammatory and oxidative and nitrosative stress (O&NS) pathways in driving changes in neuronal regulating tryptophan catabolites (TRYCATs). The essence of the association of O&NS pathways with autoimmune responses in depression is via damage to lipid membranes, anchorage molecules and functional proteins that lead to changes in their chemical structures creating new modified epitopes (neoepitopes), which are highly immunogenic. The abovementioned pathways together with decreased antioxidant levels, including zinc, coenzyme Q10, glutathione and vitamin E, and melatonin are intimately involved in different aspects of depression, including mitochondrial functions and the regulation of cAMP / circadian genes, allowing for impacts across different aspects of symptom patterning. Immuno- inflammatory and O&NS processes may additionally cause alterations in blood-brain barrier permeability and neuroprogression, that is tissue damage, including neurodegeneration and apoptosis, and decreased neurogenesis and neuroplasticity. Activation of those interconnected pathways is relevant to the pathophysiology of acute and chronic depression and the progressive course (staging) of clinical depression. This implies that compounds that target these pathways may be useful to treat acute episodes and prevent further progression of the disease. We herein review some promising compounds, such as melatonin, melatonin receptor agonists, allopregnanolone, PDE4 inhibitors, statins, aspirin, sodium benzoate, tryptophan-enriched diets, and antioxidants, including epigallocatechin gallate, curcumin, quercitin, alpha-lipoic acid and resveratrol.

Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala.

The autistic spectrum disorders (ASD) form a set of multi-faceted disorders with significant genetic, epigenetic and environmental determinants. Oxidative and nitrosative stress (O&NS), immuno-inflammatory pathways, mitochondrial dysfunction and dysregulation of the tryptophan catabolite (TRYCATs) pathway play significant interactive roles in driving the early developmental etiology and course of ASD. O&NS interactions with immuno-inflammatory pathways mediate their effects centrally via the regulation of astrocyte and microglia responses, including regional variations in TRYCATs produced. Here we review the nature of these interactions and propose an early developmental model whereby different ASD genetic susceptibilities interact with environmental and epigenetic processes, resulting in glia biasing the patterning of central interarea interactions. A role for decreased local melatonin and N-acetylserotonin production by immune and glia cells may be a significant treatment target.

Increased IL-6 trans-signaling in depression: focus on the tryptophan catabolite pathway, melatonin and neuroprogression

Depression has been conceptualized as a disorder driven by immuno-inflammatory pathways and oxidative and nitrosative stress. These factors couple to the induction of neuroregulatory tryptophan catabolites via the activation of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Oxidative damage to neoepitopes increases autoimmune responses, changing the nature of the neural substrate of recurrent depression, which leads to neuroprogression and drives treatment resistance. A number of pro-inflammatory cytokines are linked to these processes. Here, we focus on the role of interleukin (IL)-6 in depression and its associated disorders; we highlight the progress made since the first paper showing increased IL-6 levels was published 20 years ago by Maes and colleagues. When coupled with increased levels of the soluble IL-6 receptor in depression, higher levels of IL-6 may indicate increased IL-6 trans-signaling, whereby IL-6 receptor signaling occurs in cells not normally expressing the IL-6 receptor. It has been suggested that IL-6 is intimately associated with two crucial aspects of depression, as well as central inflammation more broadly. First, the regulation of the local inflammatory response via its interactions with macrophage and glia melatonin production is coupled to local epigenetic modulation via methyl CpG-binding protein 2 (MeCP2). Second, the more systemic regulation of tryptophan availability occurs via the IL-6 induction of IDO. Coupled to its role in the regulation of autoimmune associated T-helper 17 cells and IL-17 production, IL-6 has wide and differential impacts on processes driving depression and a wider range of psychiatric and neurodegenerative conditions.

The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs)

The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host's immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.

Role of immunological factors in the pathophysiology and diagnosis of bipolar disorder: Comparison with schizophrenia

Several lines of evidence point to the key role of neurobiological mechanisms and shared genetic background in schizophrenia and bipolar disorder. For both disorders, neurodevelopmental and neurodegenerative processes have been postulated to be relevant for the pathogenesis as well as dysregulation of immuno-inflammatory pathways. Inflammation is a complex biological response to harmful stimuli and it is mediated by cytokines cascades, cellular immune responses, oxidative factors and hormone regulation. Cytokines, in particular, are supposed to play a critical role in infectious and inflammatory processes, mediating the cross-talk between the brain and the immune system; they also possibly contribute to the development of the central nervous system. From this perspective, even though mixed results have been reported, it seems that both schizophrenia and bipolar disorder are associated with an imbalance in inflammatory cytokines; in fact, some of these could represent biological markers of illness and could be possible targets for pharmacological treatments. In light of these considerations, the purpose of the present paper was to provide a comprehensive and critical review of the existing literature about immunological abnormalities in bipolar disorder with particular attention to the similarities and differences with schizophrenia.

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

Background‘Encephalomyelitis disseminata’ (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS.DiscussionThere are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.SummaryThis review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.

Mitochondrial dysfunctions in Myalgic Encephalomyelitis / chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) is classified by the World Health Organization as a disorder of the central nervous system. ME/cfs is an neuro-immune disorder accompanied by chronic low-grade inflammation, increased levels of oxidative and nitrosative stress (O&NS), O&NS-mediated damage to fatty acids, DNA and proteins, autoimmune reactions directed against neoantigens and brain disorders. Mitochondrial dysfunctions have been found in ME/cfs, e.g. lowered ATP production, impaired oxidative phosphorylation and mitochondrial damage. This paper reviews the pathways that may explain mitochondrial dysfunctions in ME/cfs. Increased levels of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, and elastase, and increased O&NS may inhibit mitochondrial respiration, decrease the activities of the electron transport chain and mitochondrial membrane potential, increase mitochondrial membrane permeability, interfere with ATP production and cause mitochondrial shutdown. The activated O&NS pathways may additionally lead to damage of mitochondrial DNA and membranes thus decreasing membrane fluidity. Lowered levels of antioxidants, zinc and coenzyme Q10, and ω3 polyunsaturated fatty acids in ME/cfs may further aggravate the activated immuno-inflammatory and O&NS pathways. Therefore, it may be concluded that immuno-inflammatory and O&NS pathways may play a role in the mitochondrial dysfunctions and consequently the bioenergetic abnormalities seen in patients with ME/cfs. Defects in ATP production and the electron transport complex, in turn, are associated with an elevated production of superoxide and hydrogen peroxide in mitochondria creating adaptive and synergistic damage. It is argued that mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of ME/cfs symptoms, e.g. fatigue and post exertional malaise, and may explain in part the central metabolic abnormalities observed in ME/cfs, e.g. glucose hypometabolism and cerebral hypoperfusion.

Human immunodeficiency virus-associated depression: contributions of immuno-inflammatory, monoaminergic, neurodegenerative, and neurotrophic pathways

In the era of greatly improved pharmacological treatment of HIV infection through highly active antiretroviral therapy (HAART), HIV patients experience reduced viral loads, reduced opportunistic infections, increased CD4+ T cell count, and greater life expectancy. Although life expectancy is increased, patients often develop neurological disturbances that may persist for long periods, seriously jeopardizing quality of life and adherence to the medication protocols of HAART. For these reasons, HIV-associated neurological disorders have gained importance in both clinical and basic investigations of HIV infection. Depression is the most prevalent neuropsychiatric disorder among people living with HIV. In this review, we discuss how HIV can predispose infected individuals to depression by several interrelated mechanisms. These include inducing chronic elevation of cytokines through activation of microglia and astrocytes; decreasing monoaminergic function; inducing neurotoxicity, especially in dopaminergic neurons; and reducing brain-derived neurotrophic factor. These viral pathways interact with psychosocial factors to create the depressive state. HIV depression has a great impact on quality of life and implementation of antiretroviral therapy, and thus, recognition of these modes of action is significant for understanding HIV neuropathology and for selecting modalities for pharmacologic treatment.

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation

BackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation. MethodsWe examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale). ResultsThe incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise. DiscussionThe results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.

Th1 and Th2-like Protein Balance in Human Inflammatory Radicular Cysts and Periapical Granulomas

IntroductionChronic dental periapical lesions result from chronic inflammation of periapical tissues caused by continuous antigenic stimulation from infected root canals. Recent findings have suggested that T helper (Th) 1 and Th2-like cytokines are important in the pathogenesis of chronic periapical inflammatory diseases. However, the mechanisms regulating these immunoinflammatory pathways have not been fully elucidated. Thus, the aim of this study was to evaluate interleukin (IL)-4, IL-12, and interferon γ (IFN-γ) protein levels in human radicular cysts and periapical granulomas. MethodsArchived samples of cysts (n = 52) and granulomas (n = 27) were sectioned and submitted to immunohistochemistry to evaluate the tissue expression of IL-4, IL-12, and IFN-γ. The data were analyzed using the Mann-Whitney U test (P < .05). ResultsAn increased expression of IFN-γ was observed in radicular cysts. IL-4 expression was stronger in periapical granulomas than in radicular cysts. IL-12 was not detected in any of the samples. ConclusionsOur study showed that IFN-γ protein levels are increased in radicular cysts, whereas IL-4 expression is stronger in samples of periapical granulomas. Further studies are necessary to elucidate the signaling pathways mediated by these cytokines and to facilitate the development of more effective periapical disease management strategies.

Mechanism of Inflammation in Age-Related Macular Degeneration: An Up-to-Date on Genetic Landmarks

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment among people over 50 years of age, accounting for up to 50% of all cases of legal blindness in Western countries. Although the aging represents the main determinant of AMD, it must be considered a multifaceted disease caused by interactions among environmental risk factors and genetic backgrounds. Mounting evidence and/or arguments document the crucial role of inflammation and immune-mediated processes in the pathogenesis of AMD. Proinflammatory effects secondary to chronic inflammation (e.g., alternative complement activation) and heterogeneous types of oxidative stress (e.g., impaired cholesterol homeostasis) can result in degenerative damages at the level of crucial macular structures, that is photoreceptors, retinal pigment epithelium, and Bruch's membrane. In the most recent years, the association of AMD with genes, directly or indirectly, involved in immunoinflammatory pathways is increasingly becoming an essential core for AMD knowledge. Starting from the key basic-research notions detectable at the root of AMD pathogenesis, the present up-to-date paper reviews the best-known and/or the most attractive genetic findings linked to the mechanisms of inflammation of this complex disease.

Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Fukuda’s criteria are adequate to make a distinction between Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF), but ME/CFS patients should be subdivided into those with (termed ME) and without (termed CFS) post exertional malaise [Maes et al. 2012]. ME/CFS is considered to be a neuro-immune disease. ME/CFS is characterized by activated immuno-inflammatory pathways, including increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP. These processes may explain typical symptoms of ME/CFS, e.g. fatigue, malaise, hyperalgesia, and neurologic and autonomic symptoms. Here we hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities. Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions. All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function. Future research should examine p53 signaling in ME/CFS.

Increased autoimmune responses against auto-epitopes modified by oxidative and nitrosative damage in depression: Implications for the pathways to chronic depression and neuroprogression

ObjectiveThere is evidence that major depression is characterized by oxidative and nitrosative stress (O&NS). The aim of this study is to examine IgM-mediated autoimmune responses against a variety of modified neo-epitopes formed by O&NS damage to self-epitopes in chronic depression. MethodsSerum IgM antibodies directed against conjugated oleic and azelaic acid, malondialdehyde (MDA), phosphatidyl inositol (Pi), and conjugated nitric-oxide (NO) adducts, i.e., NO-tryptophan, NO-tyrosine, NO-arginine, and NO-cysteinyl, were determined in 33 healthy controls and 74 depressed patients subdivided into 28 patients with chronic (duration >2 year) and 46 without chronic depression. ResultsSerum IgM levels against all neoepitopes were significantly higher in depressed patients than in healthy controls. Moreover, the IgM levels were significantly higher, except Pi, in chronically depressed patients than in non-chronically depressed patients. ConclusionsDepression is characterized by IgM-related autoimmune responses directed against neo-epitopes that are normally hidden from the immune system but that became immunogenic secondary to damage by O&NS. The results show that the generation of neoantigenic determinants that lead to (auto)immune responses is strongly associated with chronic depression. DiscussionThe damage caused by O&NS to auto-epitopes and the consequent formation of O&NS modified neoantigenic determinants may increase the risk to develop depression and in particular chronic depression through transition to autoimmune reactions. This has implications for understanding the immuno-inflammatory and oxidative-autoimmune pathways that lead to chronic depression and neuroprogression in that illness.

Schizophrenia: Linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression

In 1995, the macrophage-T lymphocyte theory of schizophrenia (Smith and Maes, 1995) considered that activated immuno-inflammatory pathways may account for the higher neurodevelopmental pathology linked with gestational infections through the detrimental effects of activated microglia, oxidative and nitrosative stress (O&NS), cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of the N-methyl d-aspartate receptor (NMDAr) and glutamate production. The aim of the present paper is to review the current state-of-the art regarding the role of the above pathways in schizophrenia. Accumulating data suggest a powerful role for prenatal infection, both viral and microbial, in driving an early developmental etiology to schizophrenia. Models of prenatal rodent infection show maintained activation of immuno-inflammatory pathways coupled to increased microglia activation. The ensuing activation of immuno-inflammatory pathways in schizophrenia may activate the TRYCAT pathway, including increased kynurenic acid (KA) and neurotoxic TRYCATs. Increased KA, via the inhibition of the α7 nicotinic acetylcholine receptor, lowers gamma-amino-butyric-acid (GABA)ergic post-synaptic current, contributing to dysregulated glutamatergic activity. Hypofunctioning of the NMDAr on GABAergic interneurons will contribute to glutamatergic dysregulation. Many susceptibility genes for schizophrenia are predominantly expressed in early development and will interact with these early developmental driven changes in the immuno-inflammatory and TRYCAT pathways. Maternal infection and subsequent immuno-inflammatory responses are additionally associated with O&NS, including lowered antioxidants such as glutathione. This will contribute to alterations in neurogenesis and myelination. In such a scenario a) a genetic or epigenetic potentiation of immuno-inflammatory pathways may constitute a double hit on their own, stimulating wider immuno-inflammatory responses and thus potentiating the TRYCAT pathway and subsequent NMDAr dysfunction and neuroprogression; and b) antipsychotic-induced changes in immuno-inflammatory, TRYCAT and O&NS pathways would modulate the CNS glia-neuronal interactions that determine synaptic plasticity as well as myelin generation and maintenance.

Targeting cyclooxygenase-2 in depression is not a viable therapeutic approach and may even aggravate the pathophysiology underpinning depression

Depression is a complex progressive disorder accompanied by activation of inflammatory and Th-1 driven pathways, oxidative and nitrosative stress (O&NS), lowered antioxidant levels, mitochondrial dysfunctions, neuroprogression and increased bacterial translocation. In depression, activation of immuno-inflammatory pathways is associated with an increased risk for cardio-vascular disorder (CVD). Because of the inflammatory component, the use of cyclooxygenase 2 (COX-2) inhibitors, such as celecoxib, has been advocated to treat depression. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this selective review on the effects of COX-2 inhibitors aggravating the abovementioned pathways. COX-2 inhibitors may induce neuroinflammation, exacerbate Th1 driven responses, increase lipid peroxidation, decrease the levels of key antioxidants, damage mitochondria and aggravate neuroprogression. COX-2 inhibitors may aggravate bacterial translocation and CVD through Th1-driven mechanisms. COX-2 inhibitors may aggravate the pathophysiology of depression. Since Th1 and O&NS pathways are risk factors for CVD, the use of COX-2 inhibitors may further aggravate the increased risk for CVD in depression. Selectively targeting COX-2 may not be a viable therapeutic approach to treat depression. Multi-targeting of the different pathways that play a role in depression is more likely to yield good treatment results.

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome

This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.

MiR-375 is downregulated in epithelial cells after IL-13 stimulation and regulates an IL-13-induced epithelial transcriptome.

Interleukin 13 (IL-13)-induced epithelial gene and protein expression changes are central to the pathogenesis of multiple allergic diseases. Herein, using human esophageal squamous and bronchial columnar epithelial cells, we identified microRNAs (miRNAs) that were differentially regulated after IL-13 stimulation. Among the IL-13-regulated miRNAs, miR-375 showed a conserved pattern of downregulation. Furthermore, miR-375 was downregulated in the lung of IL-13 lung transgenic mice. We subsequently analyzed miR-375 levels in a human disease characterized by IL-13 overproduction--the allergic disorder eosinophilic esophagitis (EE)--and observed downregulation of miR-375 in EE patient samples compared with control patients. MiR-375 expression levels reflected disease activity, normalized with remission, and inversely correlated with the degree of allergic inflammation. Using a lentiviral strategy and whole-transcriptome analysis in epithelial cells, miR-375 overexpression was sufficient to markedly modify IL-13-associated immunoinflammatory pathways in epithelial cells in vitro, further substantiating interactions between miR-375 and IL-13. Taken together, our results support a key role of miRNAs, particularly miR-375, in regulating and fine-tuning IL-13-mediated responses.