in 1955 , pepys postulated that histamine ( ha ) could affect the immune response . since then , the influence of ha on immune and inflammatory reactions has been well documented . in the late 1970s and early 1980s , watanabe 's , schwartz 's , and panula 's groups in japan , france , and finland , respectively , demonstrated the presence of ha in the brain where this ancestral biogenic amine acts as a neurotransmitter and neuroimmune modulator [ 13 ] . ha is at a privileged position to display multiple pleiotropic functions in peripheral tissues and in the central nervous system ( cns ) . ha is synthesized by histidine decarboxylase ( hdc ; ec 4.1.1.22 ) from l - histidine in different cellular compartments ( mast cells , basophils , glial cells , endothelial cells , and neurons ) . ha acts through different types of ha receptors ( h1r , h2r , h3r , and h4r ) . h1r and h2r are widely distributed in most cells and tissues ; however , h3rs are mainly expressed in the cns , and h4rs are expressed in hematopoietic cells , indicating their function in neurotransmission and immunomodulation , respectively . the h3r is a recognized drug target for neuronal diseases , such as cognitive impairment , schizophrenia ( scz ) , sleep / wake disorders , epilepsy , and neuropathic pain . the organization of the brain histaminergic system shows a strategic disposition , with ha neurons located in the posterior hypothalamus , from where ascending pathways ( to the anterior hypothalamus , limbic structures ( hippocampus ) , neocortex , and subcortical structures ) and descending pathways ( to the brain stem and spinal cord ) are organized . the interplay of brain ha in neurons , endothelial cells , glia , and mast cells is fundamental for the regulation of diverse physiological functions ( neuroendocrine system , circadian rhythms , sleep - wakefulness cycle , psychomotor activity , mood , learning , cognition , appetite , and eating behavior ) ; and alterations in multicompartment brain ha are involved in several pathological conditions , such as epilepsy , stroke , anxiety , depression , psychosis , neurodegeneration , and neuroinflammatory processes [ 3 , 5 , 6 ] . brain ha is distributed in several compartments ( neuronal , glial , endothelial , and mast cells ) . mast cells are connective tissue cells , discovered by ehrlich in 1887 , which are rich in metachromatic granules containing ha , heparin , and serotonin . riley , west , and coworkers were the first to establish an association between mast cells and ha in 1953 , and benditt and colleagues showed , in 1955 , that mast cells also contained 5-hydroxytryptamine ( 5-ht ; serotonin ) . in 1953 , riley demonstrated that injection of ha releasers was followed by damage to mast cells . examples of ha releasers include compound 48/80 , mast cell - degranulating peptide ( mcd ) , polylysine , polymyxin b , dextran , phosphatidylserine , melittin , f - met - tripeptides , c5a / c3a anaphylatoxins , c4a , calcium ionophore a23187 , and many cytokines and growth factors . many , if not all , mast cells are innervated by varicose axons in different body structures , and even an  axon reflex  pathway involving mast cells was proposed in the skin by kiernan in 1965 . mast cells originate from bone marrow hematopoietic cd34 progenitor cells , which enter the circulation and migrate to distal tissues where they ultimately reside . mature mast cells are a heterogeneous population of cells with various phenotypes depending on their location . mast cells express fcri , a high - affinity ige receptor , which upon activation induces exocytosis of cytoplasmic secretory granules , de novo synthesis of lipid - derived mediators , and release of cytokines , chemokines , monoamines , and growth factors . mast cell secretory granules contain a great variety of mediators , such as histamine , serotonin , tryptase , chymase , and antizyme inhibitor 2 ( azin2 ) , an activator of polyamine biosynthesis whose catalyzing enzyme is ornithine decarboxylase . mast cells are resident in the brain and contain numerous mediators , including neurotransmitters , cytokines , and chemokines , that are released in response to a variety of natural and pharmacological triggers . brain mast cells are of two types , namely , metachromatic type i cells and normochromatic type ii cells , or neurolipomastocytoid cells . in mice devoid of mast cells ( w / w mice ) , the administration of -fluoromethylhistidine ( fmh ) , a suicide inhibitor of hdc , reduces the concentration of brain ha to nearly zero , suggesting that approximately 50% of the content of ha in the cns belongs to the nonneuronal pool [ 9 , 10 ] . the presence of mast cells in meninges and perivascular locations on the brain side of the bbb , especially in thalamic and hippocampal regions , may indicate that this cell type is relevant in neurovascular responses . the number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states . some mast cell mediators are synthesized upon activation ( e.g. , neuropeptides , cytokines ) while others are preformed and stored in granules from which they are rapidly released ( e.g. , serotonin , histamine ) . mast cells can act via autocrine and paracrine mechanisms ; their secretions can reach a large space volume , and they can migrate to critical regions influencing neuronal activity , repairing tissue damage , or aggravating inflammatory processes within the cns . these properties suggest that mast cells are poised to influence neural systems underlying behavior . using genetic and pharmacological loss - of - function models , nautiyal et al . performed a behavioral screen for arousal responses including emotionality , locomotor , and sensory components and found that mast cell - deficient kit ( sash ) mice had a greater anxiety - like phenotype than wt and heterozygote littermate control animals in the open field arena and elevated plus maze . blockade of brain , but not peripheral , mast cell activation increased anxiety - like behavior . brain mast cells might be implicated in the modulation of anxiety - like behavior and provide evidence for the behavioral importance of neuroimmune links . microglia can constitutively express ha receptors ( h1r , h2r , h3r , and h4r ) , and the expression of h1r and h4r can be selectively upregulated by ha in microglial cells in a dose - dependent manner . ha induces tnf- and il-6 release from activated microglia via h1r and h4r - mapk and the pi3k / akt - nf - kappa b signaling pathway . microglia express h2r , h3r , histidine decarboxylase , and histamine n - methyltransferase . both forskolin - induced camp accumulation and atp - induced intracellular ca transients are reduced by the h3r agonist imetit but not by the h2r agonist amthamine . ha and imetit inhibit microglial chemotaxis , phagocytosis , and lipopolysaccharide ( lps)-induced cytokine production . ha and substance p can trigger microglial activation and release of proinflammatory factors from microglia , thus contributing to the development of microglia - mediated inflammation in the brain . the interplay of brain ha in neurons , endothelial cells , glia , and mast cells is fundamental for the regulation of diverse physiological functions ( neuroendocrine system , circadian rhythms , sleep - wakefulness cycle , psychomotor activity , mood , learning , cognition , appetite , and eating behavior ) ; and alterations in multicompartment brain ha are involved in several pathological conditions [ 3 , 5 , 15 , 16 ] . ha is implicated in the control of arousal state , exerting a potent phase - shifting effect on the circadian clock in the suprachiasmatic nucleus ( scn ) . to reset the circadian clock , ha increases [ ca]i in scn neurons by activating cav 1.3 channels through h1rs and secondarily by causing ca - induced ca release from ryr - mediated internal stores . light has direct effects on sleep and wakefulness causing arousal in diurnal animals and sleep in nocturnal animals . histaminergic neurotransmission attenuates the light - induced sleep response during the dark period . using knockout ( ko ) mice lacking hdc , parmentier et al h1-receptor ko ( h1 ) mice share several characteristics with hdc ko mice , including a decrease in wakefulness after lights - off despite its normal baseline daily amount , a decreased eeg slow wave sleep ( sws)/w power ratio , and inability to maintain wakefulness in response to behavioral challenges . yu et al .   reported that gaba and ha are involved in the mechanisms of wakefulness . ha neurons in the tuberomammillary nucleus ( tmn ) of the hypothalamus form a widely projecting , wake - active network that sustains arousal . selective sirna knockdown of the vesicular gaba transporter ( vgat , slc32a1 ) in ha neurons produces hyperactive mice with an exceptional amount of sustained wakefulness . optogenetic stimulation in the caudate - putamen and neocortex of ha axonal projections from the tmn evokes tonic , extrasynaptic gabaa receptor cl currents onto medium spiny neurons and pyramidal neurons . thus , wake - active ha neurons may generate a paracrine gabaergic signal that serves to provide a brake on overactivation of ha and to increase the precision of neocortical processing . yu et al .   studied the contribution of one putative local clock in mouse histaminergic neurons in the tuberomammillary nucleus to the regulation of the sleep - wake cycle . deletion of the bmal1 ( arntl / mop3 ) clock gene from ha cells removes this variation , producing higher hdc expression and brain ha levels during the day . the consequences include more fragmented sleep , prolonged wakefulness at night , shallower sleep depth ( lower nonrapid eye movement [ nrem ]  power ) , increased nrem - to - rem transitions , hindered recovery sleep after sleep deprivation , and impaired memory . removing bmal1 from histaminergic neurons does not , however , affect circadian rhythms . there are important age- and sex - related changes in the concentration of ha and h1r in different regions of the cns [ 6 , 22 ] ( figure 1 ) . dramatic changes in ha and h1r have been reported after surgical manipulation of the neuroendocrine system ( e.g. , castration , adrenalectomy ) , clearly indicating the relevant effect that changes in the hypothalamus - pituitary - gonadal axis and hypothalamus - pituitary - adrenergic axis exert on brain ha [ 9 , 22 ] . similarly , direct interactions between the somatotropinergic system ( grh / ss - gh - igf1 ) and ha   and the vasopressinergic system and ha have been extensively demonstrated . l - histidine and ha induce a time- and dose - dependent decrease in hypothalamic interleukin-1 ( il-1 ) , and this effect is not affected by mepyramine ( h1r antagonist ) , famotidine ( h2r antagonist ) , or thioperamide ( h3r antagonist ) . the abolishment of neuronal ha by -fluoromethylhistidine , a suicide inhibitor of hdc , causes a significant decrease in the hypothalamic concentration of tnf- . important changes in the peripheral ( figure 2 ) and central levels of ha ( figure 3 ) occur in patients with different cns disorders . these changes are particularly important in alzheimer 's disease ( ad ) , where ha levels are significantly increased in most cns regions [ 6 , 27 ] ( figure 3 ) . changes in ha , tnf- , and il-1 [ 28 , 29 ] in ad correlate with cerebrovascular dysfunction and cognitive decline [ 3 , 30 ] . furthermore , improvement in cognitive function with neuroprotectants ( e.g. , cdl - choline ) [ 3133 ] or vegetal neurotrophins ( e.g. , anapsos ) [ 34 , 35 ] can reverse alterations in ha , tnf- , and il-1 levels in ad and in animal models of dementia [ 7 , 25 , 3437 ] . ad - related neurodegeneration exhibits a pathological phenotype compatible with a reactive neuroinflammatory process in which ha , tnf- , and il-1 , among many other immune effectors , are involved . there is also a correlation between microglia activation and apoe genotypes [ 38 , 39 ] ; and peripheral ha levels are also apoe - related , with the lowest levels present in patients harboring the apoe-4 allele [ 6 , 40 ] ( figures 4 and 5 ) . an association between apoe-4 and increased expression of cd95 on t cells has also been reported , suggesting that hyperexpression of fas mrna and surface fas receptor on cd45ro t lymphocytes may explain the occurrence of inflammatory cellular infiltrates in ad brain tissue . all these data together illustrate the potential role of ha as a fundamental player in ad - related neuroinflammation and other neuropsychiatric disorders . in fact , results of clinical trials with h3 antagonists such as abt-288   or gsk239512 have been recently reported . patients with different types of cns disorders exhibit significant variation in lymphocyte subsets with regard to that of the general population , indicating that alterations in brain function may alter lymphocytes and immune markers in the periphery . by flow cytometry analysis , we have studied changes in lymphocyte subpopulations and immune markers in healthy controls ( n = 374 ) and in the general population ( n = 3311 ) , as well as in patients with diverse cns disorders including anxiety ( n = 340 ) , depression ( n = 483 ) , psychosis / schizophrenia ( n = 199 ) , stroke ( n = 77 ) , alzheimer 's disease ( n = 247 ) , parkinson 's disease ( n = 81 ) , attention - deficit hyperactivity disorder ( adhd ) ( n = 47 ) , migraine ( n = 238 ) , epilepsy ( n = 81 ) , vascular dementia ( n = 215 ) , vascular encephalopathy ( associated with diabetes , hypertension , or symptomatic arteriosclerosis ) ( n = 404 ) , multiple sclerosis ( n = 22 ) , chronic cerebral insufficiency ( n = 152 ) , brain tumors ( n = 14 ) , cranial nerve neuropathy ( trigeminal neuralgia , facial palsy ) ( n = 32 ) , mental retardation ( n = 135 ) , and posttraumatic brain injury ( n = 65 )   ( table 1 ) . cd3 ( total t cells ) only showed significant differences ( p < 0.05 ) in children with mental retardation and in patients with vascular dementia . cd4 ( t helper / inducer cells ) significantly differ between controls and adhd , mental retardation , and epilepsy ; between depression and adhd , mental retardation , and epilepsy ; between migraine and adhd and mental retardation ; and between cerebrovascular insufficiency , adhd , and mental retardation . cd7 ( t cells + natural killer , nk ) differ between vascular encephalopathy and psychosis , migraine , epilepsy , and mental retardation . cd8 ( t suppressor / cytotoxic ) did not show any relevant difference among different cns pathologies with regard to controls . hla - dr ( class ii mch antigen ) exhibit significant differences between adhd and parkinson 's disease , stroke , vascular dementia , ad , and vascular encephalopathy ; between epilepsy and parkinson 's disease , stroke , vascular dementia , ad , and vascular encephalopathy ; and between mental retardation and parkinson 's disease , stroke , vascular dementia , ad , and vascular encephalopathy . cd25 ( il-2 receptors ) were found lower in adhd , mental retardation , and epilepsy with respect to controls and vascular encephalopathy . cd28 ( 6080% cd3 ) were found lower in vascular dementia and parkinson 's disease with regard to controls , anxiety , depression , psychosis , migraine , epilepsy , multiple sclerosis , and posttraumatic brain injury . cd56 ( nk cells ) were significantly increased in parkinson 's disease and vascular dementia in relation to most other groups . no significant changes were found in both cd3/hla - dr and cd4/cd8 ratios in cns disorders   ( table 1 ) . all these data together clearly reflect that brain damage and/or pathologic alterations in brain function leading to neurologic and/or psychiatric disorders can induce significant changes in peripheral lymphocytes and immune markers . this fact provides additional support to the predominant role of brain on immune function and immune mediators . recent studies bring new insights into the nature of inflammation signaling and regulation of proinflammatory genes , opening new avenues for novel therapeutic intervention in inflammatory processes . one example is the a20 protein , a cytosolic peptide that controls interactions between key ubiquitin - conjugating enzymes , thereby regulating the expression of proinflammatory genes [ 44 , 45 ] . the a20 gene locus has been associated with risk for crohn 's disease , systemic lupus erythematosus , rheumatoid arthritis , type i diabetes , psoriasis , and atherosclerosis . a20 is an important regulator of autoimmunity and a tumor suppressor for hodgkin 's lymphoma and large b cell lymphoma . a20 acts through the transcription factor nuclear factor-b ( nf-b ) to control inflammation , and nf-b regulates the expression of genes involved in inflammation and immunity . nf-b protein inhibitor ( ib ) maintains inactive nf-b in the cytoplasma of unstimulated cells . proinflammatory ligands , such as tnf- , lps , and il-1 , activate the ib kinase ( ikk ) complex to phosphorylate ibs , inducing their degradation , which releases associated nf-b to translocate into the nucleus and activate the transcription of genes that promote inflammation . one target gene is a20 ( tnfaip3 ) , a negative feedback regulator that terminates ikk and nf-b activation . shembade et al .   have reported that a20 negatively regulates inflammation by inhibiting nf-b transcription factor in the tnf receptor ( tnfr ) and toll - like receptor ( tlr ) pathways . a20 contains deubiquitinase and e3 ligase domains and has been proposed to function as a ubiquitin - editing enzyme downstream of tnfr1 by inactivating rip1 . a20 inhibits the e3 ligase activities of traf6 , traf2 , and clap1 by antagonizing interactions with the e2 ubiquitin - conjugating enzymes ubc13 and ubch5c . a20 , together with the regulatory molecule tax1bp1 , interacts with ubc13 and ubch5c and triggers their ubiquitination and proteasome - dependent degradation . these results suggest that pharmacological inhibition of the e2 ligases controlled by a20 might be beneficial in treating certain autoimmune diseases and cancer . injury causes a systemic inflammatory response syndrome ( sirs ) that is clinically similar to sepsis . cellular injury can release endogenous damage - associated molecular patterns ( damps ) that activate innate immunity . as postulated by sagan , altman , and others in the 1960s , mitochondria are evolutionary endosymbionts derived from bacteria which might bear bacterial molecular motifs . zhang et al .   have shown that injury releases mitochondrial damps ( mtds ) into the circulation with functionally important immune consequences . mtds include formyl peptides and mtdna that activate polymorphonuclear neutrophils ( pmns ) through formyl peptide receptor-1 and toll - like receptor ( tlr ) 9 , respectively . mtds promote pmn calcium flux and phosphorylation of mitogen - activated protein ( map ) kinases , thus leading to pmn migration and degranulation . the release of such mitochondrial factors by cellular injury is a key link between trauma , inflammation , and sirs . the notch1 pathway dictates activation of m1 phenotypes in isolated mouse hepatic macrophages ( hmacs ) and in a murine macrophage cell line by coupling transcriptional upregulation of m1 genes with metabolic upregulation of mitochondrial oxidative phosphorylation and ros ( mtros ) to augment induction of m1 genes . enhanced mitochondrial glucose oxidation is achieved by increased recruitment of the notch1 intracellular domain ( nicd1 ) to nuclear and mitochondrial genes that encode respiratory chain components and by notch - dependent induction of pyruvate dehydrogenase phosphatase 1 ( pdp1 ) expression , pyruvate dehydrogenase activity , and glucose flux to the tca cycle . inhibition of the notch pathway or pdp1 knockdown abrogates glucose oxidation , mtros , and m1 gene expression . conditional notch1 deficiency in the myeloid lineage attenuates hmac m1 activation and inflammation in a murine model of alcoholic steatohepatitis and markedly reduces lethality following endotoxin - mediated fulminant hepatitis in mice . monocyte tracking requires notch1 for the migration of blood monocytes into the liver and subsequent m1 differentiation . according to the elegant studies reported by xu et al . .   demonstrated for the first time that early hyperlipidemia promotes endothelial cells ( ec ) activation before monocyte recruitment via a caspase-1-sirtuin 1-activator protein-1 pathway , which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations . using new apolipoprotein e ( apoe)/caspase-1 double knockout mice , they observed that ( i ) early hyperlipidemia induced caspase-1 activation in apoe mouse aorta ; ( ii ) caspase-1/apoe mice attenuated early atherosclerosis ; ( iii ) caspase-1/apoe mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment ; and ( iv ) caspase-1/apoe mice had decreased ec activation , including reduced adhesion molecule expression and cytokine secretion . oxidized lipids activated caspase-1 and promoted pyroptosis in ec by a reactive oxygen species mechanism . caspase-1 inhibition resulted in accumulation of sirtuin 1 in the apoe aorta , and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway . tristetraprolin ( ttp ) is an anti - inflammatory protein that acts by binding to ares in its target mrnas , such as tnf mrna , and promoting their deadenylation and decay . tnf released from inflammatory cells can then stimulate gene expression in tissue cells , such as fibroblasts . the decay rates of transcripts encoded by several early - response genes , including cxcl1 , cxcl2 , ier3 , ptgs2 , and lif , are significantly slowed in ttp - deficient fibroblasts after tnf stimulation . these changes are associated with ttp - dependent increases in cxcl1 , cxcl2 , and ier3 protein levels . the ttp - susceptible transcripts contain multiple , conserved , closely spaced , potential ttp binding sites in their 3-utrs . wt ttp , but not a nonbinding ttp zinc finger mutant , binds to rna probes that are based on the mrna sequences of cxcl1 , cxcl2 , ptgs2 , and lif . ttp - promoted decay of transcripts encoding chemokines and other proinflammatory mediators is thus a critical posttranscriptional regulatory mechanism in the response of secondary cells , such as fibroblasts , to tnf released from primary immune cells . neutrophils have the capacity to package a variety of cytokines into cytoplasmic granules for subsequent release upon inflammatory conditions . the rapid secretion of cytokines orchestrates the action of other immune cells at the infection site and contributes to the development and chronicity of inflammatory diseases . naegelen et al .   studied the intracellular snare machinery responsible for the regulation of cytokine secretion and degranulation and demonstrated that syntaxin-3 ( stx3 ) is required for the maximal release of il-1 , il-1 , il-12b , and ccl4 without alteration of other cytokine secretions in dhl-60 cells . stx3 is involved in mmp-9 exocytosis from gelatinase granules , where stx3 is partly localized . the secretion of il-1 , il-1 , il-12b , and ccl4 occurs during gelatinase degranulation , a process controlled by stx3 which has an essential role in trafficking pathways of cytokines in neutrophil granulocytes . sestrins ( sesns ) are conserved antioxidant proteins that accumulate in cells in response to various stresses . yang et al .   investigated whether sesn2 regulates toll - like receptor- ( tlr- ) mediated inflammatory signaling and sought to identify the molecular mechanism responsible . sesn2 almost completely inhibits lps - induced no release and inos expression . a gene knockdown experiment confirmed the role of sesn2 in lps - activated raw264.7 cells . sesn2 prevents lps - elicited cell death and ros production via inhibition of nadph oxidase . nf-b and ap-1 are redox - sensitive transcription factors that regulate the expressions of diverse inflammatory genes . sesn2 specifically inhibits ap-1 luciferase activity and its dna binding , but not those of nf-b . ap-1 inhibition by sesn2 is due to a lack of jnk , p38 , and c - jun phosphorylation . sesn2 protects galactosamine ( gal)/lps - induced liver injury in mice infected with a recombinant adenovirus sesn2 ( ad - sesn2 ) . ad - sesn2 causes less severe hepatic injury as supported by decreases in the alt , ast , and hepatocyte degeneration . sesn2 inhibits tlr - induced proinflammatory signaling and protects cells by inhibiting jnk- or p38-mediated c - jun phosphorylation . abundant data provide support to a multidimensional crosstalk among neural , endocrine , and immune signals probably contributing to global homeostasis , constant surveillance to maintain control against exogenous and/or endogenous stressors , brain maturation and development , neuroprotection , and fine - tuning of brain functions associated with higher activities of the cns . neuroimmune dysfunction may be part of the pathogenesis of different cns disorders , including mental disorders ( scz , depression , anxiety , and posttraumatic stress disorder ) , neurodegenerative disorders ( ad , parkinson 's disease , and prion disease ) , brain infections , stroke , brain tumors , and demyelinating disorders . it is likely that the neuroimmune system acts as a regulatory , defense system which reacts against noxious stimuli that endanger brain function stability and optimum performance . in this context , neuroimmune activation in cns pathology might be a double - faced reactive phenomenon : ( i ) neuroprotective , when the stimulus activating the neuroimmune cascade is able to neutralize tissue damage and/or brain dysfunction and ( ii ) neurotoxic , when the reactive neuroinflammatory event is persistent and becomes an autoaggression which magnifies the damage . this sword of damocles ( dual role ) hanging over the cns and other peripheral tissues under central control must be exquisitely balanced to avoid dangerous decompensation ( dominance of neurotoxic effects over neuroprotective effects ) . this homeostatic equilibrium can be maintained by the interplay of different cytokines , chemokines , neurotransmitters , neuropeptides , neurohormones , and pleiotropic substances such as histamine . this biogenic amine , acting on different receptors or emanating from different sources ( neuronal histamine versus nonneuronal histamine ) can exert antagonistic effects ( neurotrophic versus neurotoxic ) on neuronal targets inducing either protection or damage . although there was a growing interest for neuroimmune function and neuroinflammation during the past two decades , with relevant scientific contributions to the field , our impression is that the present knowledge on neuroimmune mechanisms and their pathological consequences is still at a very primitive stage . therapeutic intervention to halt progression of deleterious neuroinflammatory reactions in cns disorders is a major challenge for molecular psychoneuropharmacology in the future .