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Background In humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis. Methods We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis. Results Both concentrations of interferon-α decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-α increased the expression of interferon-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and interleukin-6 (IL-6) via activation of STAT1. Like interferon-α, co-treatment with a combination of ISG15, USP18, and IL-6 was able to reduce neurogenesis and enhance apoptosis via further downstream activation of STAT1. Further experiments showed that ISG15 and USP18 mediated the interferon-α-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferon-α-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-α regulated pathways involved in oxidative stress and immune response (e.g., Nuclear Factor (erythroid-derived 2)-like 2 [Nrf2] and interferon regulatory factor [IRF] signaling pathway), neuronal formation (e.g., CAMP response element-binding protein [CREB] signaling), and cell death regulation (e.g., tumor protein(p)53 signaling). Conclusions We identify novel molecular mechanisms mediating the effects of interferon-α on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.

Highlights • Inflammation and reduced neurogenesis are associated with the pathophysiology of depression. • IL-1β decreased neurogenesis in human hippocampal progenitor cells. • EPA, DHA, sertraline and venlafaxine prevented the IL-1β-induced reduction in neurogenesis. • EPA and DHA reversed the IL-1β-induced increase in kynurenine levels. • EPA, DHA, sertraline and venlafaxine decreased the upregulation of IDO and KMO mRNA., Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) β, a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3 days and further differentiate for 7 days in the presence of IL-1β (10 ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1 µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1 µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10 µM) or docosahexaenoic acid (DHA, 10 µM). Co-incubation with each of these compounds reversed the IL-1β-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1β-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1β-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1β, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.

Background:\ud In humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis.\ud \ud Methods:\ud We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis.\ud \ud Results:\ud Both concentrations of interferon-α decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-α increased the expression of interferon-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and interleukin-6 (IL-6) via activation of STAT1. Like interferon-α, co-treatment with a combination of ISG15, USP18, and IL-6 was able to reduce neurogenesis and enhance apoptosis via further downstream activation of STAT1. Further experiments showed that ISG15 and USP18 mediated the interferon-α-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferon-α-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-α regulated pathways involved in oxidative stress and immune response (e.g., Nuclear Factor (erythroid-derived 2)-like 2 [Nrf2] and interferon regulatory factor [IRF] signaling pathway), neuronal formation (e.g., CAMP response element-binding protein [CREB] signaling), and cell death regulation (e.g., tumor protein(p)53 signaling).\ud \ud Conclusions:\ud We identify novel molecular mechanisms mediating the effects of interferon-α on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.

Description of measures included in the questionnaire of CoTaSS 2. Table S2. Number of participants for each component and respective response rates. (DOCX 43Â kb)

Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) β a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3 days and further differentiate for 7 days in the presence of IL-1β (10 ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1 µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1 µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10 µM) or docosahexaenoic acid (DHA, 10 µM). Co-incubation with each of these compounds reversed the IL-1β-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1β-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1β-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1β, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.

Highlights • Salivary CRP predicts poorer executive functioning in children aged 11–14 years. • The association is not confounded or moderated by concurrent psychopathology. • Findings have implications for interventions targeting cognitive deficits. • Salivary CRP can be used to investigate inflammation-brain function relationships., Elevated C-reactive protein (CRP), a non-specific biomarker of systemic bodily inflammation, has been associated with more pronounced cognitive impairments in adults with psychiatric disorders, particularly in the domains of memory and executive function. Whether this association is present in early life (i.e., the time at which the cognitive impairments that characterise these disorders become evident), and is specific to those with emerging psychiatric disorders, has yet to be investigated. To this end, we examined the association between salivary CRP and cognitive function in children aged 11–14 years and explored the moderating effect of psychopathology. The study utilised data from an established longitudinal investigation of children recruited from the community (N = 107) that had purposively over-sampled individuals experiencing psychopathology (determined using questionnaires). CRP was measured in saliva samples and participants completed assessments of cognition (memory and executive function) and psychopathology (internalising and externalising symptoms and psychotic-like experiences). Linear regression models indicated that higher salivary CRP was associated with poorer letter fluency (β = −0.24, p = 0.006) and scores on the inhibition (β = −0.28, p = 0.004) and inhibition/switching (β = −0.36, p

Abnormal hypothalamic-pituitary-adrenal (HPA) axis function, as indexed by elevated diurnal cortisol levels and/or a blunted cortisol awakening response (CAR), has been observed among patients with first episode psychosis and associated with neurocognitive deficits in this population. However, the extent to which these features precede illness onset is unclear. The current study aimed to determine whether children who are at putatively elevated risk for psychosis because they present multiple antecedents of schizophrenia (ASz), and high-risk children with a family history of illness (FHx), are characterized by abnormal cortisol levels when compared with their typically developing (TD) peers. A further aim was to investigate the extent to which cortisol levels are associated with psychosocial stress and neurocognitive function. Thirty-three ASz children, 22 FHx children, and 40 TD children were identified at age 9–12 years using a novel community-based screening procedure or as relatives of individuals with schizophrenia. All participants were antipsychotic-naive and not currently seeking treatment for their symptoms. At age 11–14 years, participants provided salivary cortisol samples and completed psychosocial stress measures and tests of memory and executive function. Results indicated that FHx children, but not ASz children, were characterized by a blunted CAR relative to their TD peers (effect size = −0.73, p = 0.01) that was not explained by psychosocial stress exposure or by distress relating to these experiences. Neither FHx nor ASz children were characterized by elevated diurnal cortisol. Among both FHx and ASz children, more pronounced HPA axis function abnormalities (i.e., higher diurnal cortisol levels and greater blunting of the CAR) were associated with poorer performance on tests of verbal memory and executive function. These findings support the notion that at least some HPA axis abnormalities described in psychosis precede illness onset, rather than being a subsequent epiphenomenon. We speculate that the blunted CAR may constitute an early (potentially genetically mediated) marker of psychosis vulnerability, whilst elevated diurnal cortisol levels may emerge only proximally to disease onset.

The immune system plays an important role in the communication between the human body and the environment, in early development as well as in adulthood. Per se, research has shown that factors such as maternal stress and nutrition as well as maternal infections can activate the immune system in the infant. A rising number of research studies have shown that activation of the immune system in early life can augment the risk of some psychiatric disorders in adulthood, such as schizophrenia and depression. The mechanisms of such a developmental programming effect are unknown; however some preliminary evidence is emerging in the literature, which suggests that adult hippocampal neurogenesis may be involved. A growing number of studies have shown that pre- and postnatal exposure to an inflammatory stimulus can modulate the number of proliferating and differentiating neural progenitors in the adult hippocampus, and this can have an effect on behaviours of relevance to psychiatric disorders. This review provides a summary of these studies and highlights the evidence supporting a neurogenic hypothesis of immune developmental programming.

Background Human serum albumin (HSA) is an abundant plasma protein that binds a wide variety of hydrophobic ligands including fatty acids, bilirubin, thyroxine and hemin. Although HSA-heme complexes do not bind oxygen reversibly, it may be possible to develop modified HSA proteins or heme groups that will confer this ability on the complex. Results We present here the crystal structure of a ternary HSA-hemin-myristate complex, formed at a 1:1:4 molar ratio, that contains a single hemin group bound to subdomain IB and myristate bound at six sites. The complex displays a conformation that is intermediate between defatted HSA and HSA-fatty acid complexes; this is likely to be due to low myristate occupancy in the fatty acid binding sites that drive the conformational change. The hemin group is bound within a narrow D-shaped hydrophobic cavity which usually accommodates fatty acid; the hemin propionate groups are coordinated by a triad of basic residues at the pocket entrance. The iron atom in the centre of the hemin is coordinated by Tyr161. Conclusion The structure of the HSA-hemin-myristate complex (PDB ID 1o9x) reveals the key polar and hydrophobic interactions that determine the hemin-binding specificity of HSA. The details of the hemin-binding environment of HSA provide a structural foundation for efforts to modify the protein and/or the heme molecule in order to engineer complexes that have favourable oxygen-binding properties.

El objetivo fundamental de este trabajo de Tesis fue el desarrollo de rutassintéticas para la obtención de tioazúcares cuyo azufre se encuentra incorporado enun anillo de cinco miembros. Estas moléculas podrían resultar biológicamenteactivas, o podrían emplearse como precursores para la síntesis de productosnaturales, o de análogos azufrados de los mismos. El reemplazo del oxigeno delciclo por azufre induce interesantes cambios en las propiedades y reactividadquímica. Desde el punto de vista bioquímico, se ha descripto que los tioazúcaresactúan como antimetabolitos, inhibidores enzimáticos o inductores de enzimashidrolíticas de ()-glicósidos. Los estudios de síntesis, reactividad y actividad biológica se han realizadoprincipalmente sobre 5-tiopiranosas, mientras que la química y bioquímica de las 4-tiofuranosas y sus derivados es menos conocida. Por ello, se plantearon comoobjetivos: primeramente la síntesis de la 4-tio-L-ramnosa, y luego la síntesis dealdopentono-l,4-tiolactonas. Cabe destacar que en la literatura no se encontrabadescripto ningún procedimiento sintético para obtener estas moléculas. Dado que la L-ramnosa se encuentra frecuentemente formando parte dellipopolisacárido de bacterias Gram negativas, su análogo azufrado, la 4-tio-L-ramnosa (190), podría resultar un potencial inhibidor de sistemas enzimáticos dedichas bacterias. Esta síntesis resultaba de interés pues complementaría los estudiosrealizados en nuestro laboratorio sobre la reactividad de 4-sulfonatos derivados demonosacáridos de distinta configuración, y con diferentes grupos protectores enposición 2 y 3, frente a la reacción de sustitución con nucleófilos precursores delgrupo tiol. La estrategia sintética empleada para la síntesis de 190, a partir de L-ramnosa, consistió en la obtención del metil α-L-ramnopiranósido, cuyos HO-2 y HO-3 se protegieron por acetonación. Con el objeto de invertir la configuración de C-4 se oxidó el hidroxilo libre (HO-4) del metil 2,3-O-isopropilidén-α-L-ramnopiranósído (164) y el carbonilo generado se redujo estereoselectivamente con NaBH4,para obtener el metil 6-desoxi-2,3-O-isopropilidén-α-L-talopiranósido (167). Se prepararon diferentes 4-O-sulfonil derivados de 167 [(mesilato (168),nosilato (169) y triflato (171)] para analizar la reactividad en la posterior etapa desustitución. Los intentos de sustitución del grupo sulfonato de 168, 169 y 171 por KSCN resultaron infructuosos. Se consideró que el anillo dioxolano fusionado conel ciclo piranósico introducía mayor rigidez en el sistema que si HO-2 y HO-3 sederivatizaban, por ejemplo, como acetato. Una molécula más flexible podría adoptaruna conformación adecuada para la sustitución nucleófilica sobre C-4. Seprepararon pues el metil 2,3-di-O-acetil-6-desoxi-4-O-[p-nitrobencén)sulfonil]α- L-talopiranósido (175) y el metil 2,3-di-O-acetil-6-desoxi-4-O-trifluorometansulfonil-α-L-talopiranósido (176). El triflato 176 experimentó la sustitución por KSCN, conduciendo al tiociano derivado de configuración mano (177) conrendimiento moderado (53%). La resistencia de los diversos derivados sulfoniladosde la serie talo a la reacción de sustitución del C-4 se justificó considerando unefecto repulsívo β-cis-axial, que operaría en el estado de transición entre el gruposaliente (sulfonato) y el sustituyente axial de C-2. Por reducción del 4-tiocianato deconfiguración L-mano (177) se obtuvo el tiol piranósico 183, el cual por acetólisisprodujo el tetraacetato piranósico 185 como único producto. La desacetilación de 185 condujo a la 4-tio-L-ramnosa (190), en su configuración furanósica, inusualpara una hexosa. Por acetilación de 190 se obtuvo la mezcla anomérica de lostetraacetatos furanósicos 191 y 192. En base a las constantes de acoplamiento (J)entre los protones del anillo furanósico se realizó su análisis conformacional,mediante el procedimiento previamente desarrollado en este laboratorio, el cualindicó que ambos anómeros (191 y 192) se encuentran poblando la región 2T3 delitinerario pseudorotacional. Por otra parte, nuestro interés en la sintesis de tiolactonas surgió de ladiversidad de aplicaciones en síntesis asimétrica de los anillos lactónicos de 5miembros, en particular de la D-ribono-l,4-lactona, utilizada como precursora denumerosos productos naturales. Se ha descripto el uso de ésta para la construcciónde estructuras cíclicas y acíclicas, de ciclopentenonas quirales empleadas en lapreparación de nucleósidos carbocíclicos y de sistemas oxabicíclicos relacionadosestructuralmente con las prostaciclinas. La 4-tio-D-ribono-1,4-lactona (193)constituiría un compuesto de partida conveniente para la síntesis de productosnaturales, o sus análogos azufrados. El análisis retrosintético de la 4-tio-D-ribono-l,4-lactona (193) sugería unprecursor con la configuración de C-4 invertida, por lo cual la L-lixono-l,4-lactonaresultaba un compuesto de partida conveniente. Puesto que ésta no es comercial, separtió de la L-gulono-l,4-lactona (196), la cual presenta la misma relaciónestereoquímica en todos los carbonos del anillo pero con un átomo de carbono másen la cadena lateral. Por di-O-isopropilidenación de 196 e hidrólisis regioselectiva seobtuvo la 2,3-O-isopropilidén-L-gulono-l,4-lactona (198), la cual se oxidó con IO4-para degradar la cadena lateral, con formación de un aldehído en C-5. Por reducciónquimioselectiva con NaBH3CN a pH 4 se obtuvo la 2,3-O-isopropilidén-L-lixono1,4-lactona (203), cuyo HO-5 se derivatizó como tosilato. La 2,3-O-isopropilidén-5- O-(p-toluensulfonil)-L-lixono-1,4-lactona (204) reaccionó con NaMeO, el cualindujo la apertura del anillo lactónico por ataque al carbonilo para dar el éstermetílico. Simultáneamente el HO-4 desplazó al tosilato de C-5, originando el 4,5-epóxido 205. Este compuesto se convirtió, por reacción con tiourea, en el 4,5-epitioderivado 206, con inversión de la configuración del C-4 (serie D-ribo). Elpaso siguiente consistió en la apertura regioselectiva del anillo tiirano por acción deun nucleófilo sobre el C-5 de manera que el grupo S- generado promoviera latiolactonización. Así, por reacción con KOAc-HOAc en DMF se obtuvo la 5-O-acetil-2,3-()-isopropilidén-4-tio-D-ribono-l,4-lactona (207), y por hidrólisis ácidade los grupos protectores, la 4-tío-D-ribono-l,4-lactona (193), con un rendimientototal del 20% a partir de 196 (37% a partir de 200). Con el propósito de verificar si la metodología empleada anteriormente podíaextenderse a la síntesis de otras tiolactonas, se procedió a sintetizar la 4-tio-L-lixono-l,4-lactona (209) a partir de D-ribono-l,4—lactona (60). La tiolactona deconfiguración lixo resultaba además de interés porque difiere de su diastereoisómera 193 en la configuración de C-4, y es este carbono el que actúa como centroestereogénico en numerosas síntesis asirnétricas que emplean aldonolactonas comoprecursores quirales. Por tratamiento de la 2,3-()-isopropilidén-5-O-(p-toluensulfonil)—D-ribono1,4-lactona (82) con NaMeO se obtuvo el derivado oxirano 212. El epóxido de 212se convirtió en el tiirano 213 por reacción con tiourea. En este proceso se produjoinversión de C-4, y en el paso siguiente el metil 4,5-didesoxi-4,5-epitio-2,3-O-isopropilidén-L-lixonato de metilo (213) experimentó apertura del anillo tiirano ytiolactonización por calentamiento con KOAc-DMF, para dar la 5-0-acetil-2,3-O-isopropilidén-4-tio-L-lixono-1,4-lactona (214). Por remoción de los gruposprotectores se obtuvo la 4-tio-L-lixono-1,4-lactona (209), con un rendimiento del 32% a partir de 60. Los derivados 2,3-insaturados de aldonolactonas, denominados comúnmentebutenólidos (2-butén-4-ólidos) son compuestos versátiles de amplio uso en síntesis. Por ello, se planteó como última meta de este trabajo la obtención de 2-butén-4-tiólidos a partir de las tioaldonolactonas preparadas previamente. En primera instancia se procedió a proteger selectivamente el hidroxiloprimario de las tiolactonas 193 y 209, empleándose al ter-butildifenilsilano comogrupo protector. Se aplicaron luego las siguientes reacciones a los derivados 5-0-sililados 220 y 225, con la finalidad de convertir en un doble enlace al sistema diolde C-2, C-3: i) tratamiento con N,N-dimetilfonnamida dimetil acetal, seguido de la eliminacióndel anillo 2-dimetilamino-l,3-dioxolano de 221 y 228 por pirólisis con Ac2O, o porformación de la sal de amonio cuatemaria (por tratamiento con Mel) y posteriorpirólisis.ii) preparación de los tionocarbonatos 222 y 226, y eliminación reductiva con Ni-Raney;iii) síntesis de los derivados 2,3-di-O-acetilado (233) y 2,3-di-O-benzoilado (234)para realizar una eliminación con Sml2. Mediante los procedimientos ii) y iii) se obtuvieron los derivadostiobutenólidos 223 y 227 con rendimientos aceptables. El poder rotatorio de estosproductos resultó, como era de esperar, de signo contrario y de aproximadamente elmismo valor. Sin embargo, el valor absoluto del poder rotatorio registrado resultaballamativamente bajo si se comparaba con el de butenólidos análogos oxigenados,sugiriendo racemización durante la eliminación. Se intentó determinar la purezaóptica de 223 y 227 mediante métodos fisicos (ccd con selector quiral ydesplazamiento de las señales de RMN-'H por complejos de lantánidos con ligandosquirales), pero los resultados no fueron concluyentes. Se recurrió entonces a unatransformación química, procediéndose a hidrogenar (Pd/C) los tiobutenólidos 223 y 227, pero también en este caso el valor absoluto del poder rotatorio de las 2,3-didesoxi-l,4-tiolactonas obtenidas (224 Consulte el resumen completo en el documento. Fil: Zunszain, Patricia Ana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Summary Abnormal hypothalamic-pituitary-adrenal (HPA) axis function, as indexed by elevated diurnal cortisol levels and/or a blunted cortisol awakening response (CAR), has been observed among patients with first episode psychosis and associated with neurocognitive deficits in this population. However, the extent to which these features precede illness onset is unclear. The current study aimed to determine whether children who are at putatively elevated risk for psychosis because they present multiple antecedents of schizophrenia (ASz), and high-risk children with a family history of illness (FHx), are characterized by abnormal cortisol levels when compared with their typically developing (TD) peers. A further aim was to investigate the extent to which cortisol levels are associated with psychosocial stress and neurocognitive function. Thirty-three ASz children, 22 FHx children, and 40 TD children were identified at age 9–12 years using a novel community-based screening procedure or as relatives of individuals with schizophrenia. All participants were antipsychotic-naive and not currently seeking treatment for their symptoms. At age 11–14 years, participants provided salivary cortisol samples and completed psychosocial stress measures and tests of memory and executive function. Results indicated that FHx children, but not ASz children, were characterized by a blunted CAR relative to their TD peers (effect size = −0.73, p = 0.01) that was not explained by psychosocial stress exposure or by distress relating to these experiences. Neither FHx nor ASz children were characterized by elevated diurnal cortisol. Among both FHx and ASz children, more pronounced HPA axis function abnormalities (i.e., higher diurnal cortisol levels and greater blunting of the CAR) were associated with poorer performance on tests of verbal memory and executive function. These findings support the notion that at least some HPA axis abnormalities described in psychosis precede illness onset, rather than being a subsequent epiphenomenon. We speculate that the blunted CAR may constitute an early (potentially genetically mediated) marker of psychosis vulnerability, whilst elevated diurnal cortisol levels may emerge only proximally to disease onset.

Background: The endocannabinoid (eCB) system, an endogenous lipid signaling system, appears to be dysregulated in depression. The role of endocannabinoids (eCBs) as potent immunomodulators, together with the accumulating support for a chronic low-grade inflammatory profile in depression, suggests a compelling hypothesis for a fundamental impairment in their intercommunication, in depression. Objective: We aim to review previous literature on individual associations between the immune and eCB systems and depression. It will focus on peripheral and central mechanisms of crosstalk between the eCB and immune systems. A potential dysregulation in this crosstalk will be discussed in the context of depression. Results: Investigations largely report a hypoactivity of the eCB system and increased inflammatory markers in individuals with depression. Findings depict a multifaceted communication whereby immunocompetent and eCB-related cells can both influence the suppression and enhancement of the other's activity in both the periphery and central nervous system. A dysregulation of the eCB system, as seen in depression, appears to be associated with central and peripheral concentrations of inflammatory agents implicated in the pathophysiology of this illness. Conclusion: The eCB and immune systems have been individually associated with and implicated in pathogenic mechanisms of depression. Both systems tightly regulate the other's activity. As such, a dysregulation in this crosstalk has potential to influence the onset and maintenance of this neuropsychiatric illness. However, few studies have investigated both systems and depression conjointly. This review highlights the demand to consider joint eCB-immune interactions in the pathoetiology of depression.