Rodrigo Pacheco

Fundación Ciencia Para la Vida · Biomedicina

Introduction Gut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters...

Dopamine has emerged as an important regulator of immunity. Recent evidence has shown that signalling through low-affinity dopamine receptors exerts anti-inflammatory effects, whilst stimulation of high-affinity dopamine receptors potentiates immunity in different models. However, the dopaminergic regulation of CD8+ T-cells in anti-tumour immunity...

Background: Dopamine (DA) affects immune functions in healthy subjects and during disease by acting on D1-like (D1 and D5) and D2-like (D2, D3 and D4) dopaminergic receptors (DR), however its effects on human polymorphonuclear leukocytes (PMN) are still poorly defined. Methods: We investigated DR expression in human PMN and the ability of DA to...

Background Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4 ⁺ T-cell-driven autoimmune response to central nervous system (CNS) deri...

Background Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by CD8 ⁺ effector T-cells and downregulated by CD4 ⁺ T-cells. However, the molecular mechanism by which urushiols stimulate innate immunity in the initial stages of this allergic reaction is poorly understood. Here we explore the sub-cellular mechanisms...

Current evidence indicates that neurodegeneration of dopaminergic neurons of the substantia nigra associated to Parkinson’s disease is a consequence of a neuroinflammatory process in which microglial cells play a central role. The initial activation of microglial cells is triggered by pathogenic protein inclusions, which are mainly composed by α-sy...

Fluoxetine is often prescribed to treat depression during pregnancy. Rodent studies have shown that fluoxetine exposure during early development can induce persistent changes in the emotional behavior of the offspring. However, the effects of prenatal fluoxetine on memory have not been elucidated. This study evaluates the memory of adult male offsp...

Background and aims: CD4+ T-cells constitute central players in inflammatory bowel diseases (IBD), driving inflammation in the gut-mucosa. Current evidence indicates that CCR9 and the integrin α4β7 are necessary and sufficient to imprint colonic homing on CD4+ T-cells upon inflammation. Interestingly, dopaminergic signalling has been previously in...

Dendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients indicated that gut inflammation in IBD is driven mainly by...

The renin-angiotensin system (RAS) is a fundamental regulator of blood pressure and has emerged as an important player in the control of inflammatory processes. Accordingly, imbalance on RAS components either systemically or locally might trigger the development of inflammatory disorders by affecting immune cells. At the same time, alterations in t...

Evidence from inflammatory bowel diseases (IBD) patients and animal models has indicated that gut inflammation is driven by effector CD4⁺ T-cell, including Th1 and Th17. Conversely, Treg seem to be dysfunctional in IBD. Importantly, dopamine, which is abundant in the gut mucosa under homoeostasis, undergoes a sharp reduction upon intestinal inflamm...

Background: Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of adaptive and innate immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervo...

Multiple sclerosis (MS) involves a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Previous evidence has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) in mouse models of MS re-stimulating CD4+ T-cells in the CNS as well as regulating the T-cell response by mean of inflammat...

Background. Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of adaptive and innate immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4⁺ T-cell-driven autoimmune response to central nervo...

Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported i...

Dopamine has emerged as a fundamental regulator of inflammation. In this regard, it has been shown that dopaminergic signalling pathways are key players promoting homeostasis between the central nervous system and the immune system. Dysregulation in the dopaminergic system affects both innate and adaptive immunity, contributing to the development o...

Background: Neuroinflammation constitutes a pathogenic process leading to neurodegeneration in several disorders, including Alzheimer's disease, Parkinson's disease (PD) and sepsis. Despite microglial cells being the central players in neuroinflammation, astrocytes play a key regulatory role in this process. Our previous results indicated that pha...

Dendritic cells (DCs) have the ability to induce tolerance or inflammation in response to self-antigens, which makes them fundamental players in autoimmunity. In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4⁺ T-cells, thus promoting autoimmun...

Neuroinflammation constitutes a fundamental process involved in Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4⁺ T-cells infiltrate the brain in PD, where they play a critical role...

Parkinson's disease (PD) is a neurodegenerative disorder affecting mainly the dopaminergic neurons of the nigrostriatal pathway, a neuronal circuit involved in the control of movements, thereby the main manifestations correspond to motor impairments. The major molecular hallmark of this disease corresponds to the presence of pathological protein in...

Background: Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased dur...

A number of studies have shown pharmacologic evidence indicating that stimulation of type I dopamine receptor (DR), favors T-helper-17 (Th17)-mediated immunity involved in experimental autoimmune encephalomyelitis (EAE) and in some other inflammatory disorders. Nevertheless, the lack of drugs that might discriminate between DRD1 and DRD5 has made t...

The dual potential to promote tolerance or inflammation to self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. Previous results have shown that stimulation of dopamine receptor D5 (DRD5) in DCs potentiates their inflammatory behaviour, favouring the development of experimental autoimmune encephalomyelitis (EAE). Here, we...

Background: The dual potential to promote tolerance or inflammation when facing self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. There is an association between smoking and DCs maturation in patients with rheumatoid arthritis (RA). However, ethnicity is a key factor in autoimmune disorders. Aim: To evaluate phenotypic...

Increasing evidence shows that antigen-presenting cells (APCs) are involved in the development of inflammation associated to hypertension. However, the potential role of APCs in the modulation of renal sodium transport has not been addressed. We hypothesized that APCs participate in renal sodium transport and, thus, development of high blood pressu...

Dendritic cell (DC) trafficking from peripheral tissues to lymph nodes (LNs) is a key step required to initiate T cell responses against pathogens as well as tumors. In this context, cellular membrane protrusions and the actin cytoskeleton are essential to guide DC migration towards chemotactic signals. Caveolin-1 (CAV1) is a scaffolding protein th...

Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 si...

Gal-8 expression revealed by LacZ histochemistry in the mouse brain. Brain sections of the heterocygous knock-in Lgals8+/- mice with positive reaction for β-gal histochemistry are listed as regions considered to express Gal-8. (PDF)

Raw data of Fig 1 and Table 1. Daily clinical score of EAE Lgals8+/+ versus Lgals8-/- mice, induced by immunization of an emulsion containing 150 μg of MOG35-55 peptide (MOGp) in 8-12-week-old Lgals8-/- and Lgals8+/+ mice. Daily monitored clinical scale of EAE symptoms: 0, no clinical signs; 1, loss of tail tone; 2, flaccid tail; 3, incomplete para...

Raw data of Fig 2. Fig 2A: FACS-analyzed frequencies of immune cell subpopulations in splenocytes from 8-12-week-old female Lgals8+/+ (WT) and Lgals8-/- (KO) mice. Table 2A: Frequencies of T cells (CD4+), B cells (CD19+), CD8+ T cells and dendritic cells (CD11c+). Table 2B: CD4+ T cell subpopulations Th1, Th2 and Th17. For polyclonal T cell activat...

Raw data of Fig 4. Splenocytes isolated from Lgals8+/+ (WT) and Lgals8-/- (KO) mice analyzed at steady state for total Tregs (Foxp3+), CXCR3+ and CCR6+ frequency in the Treg (Foxp3+ CD4+) population. Upper Table: Total Tregs obtained from five WT and five Gal8-KO mice (upper table). Middle Table: CXCR3+CCR6-. Bottom Table: CXCR3-CCR6+. Analysis fro...

Raw data of Fig 5 and Table 2: Daily clinical score of EAE Gal-8-treated versus vehicle–treated WT mice. EAE was induced in wild-type C57BL/6J mice and simultaneously treated (i.p.) with either 100 μg recombinant Gal-8 or PBS (control group) during 20 consecutive days. EAE symptoms monitored daily using the following scale: 0, no clinical signs; 1,...

Raw data of Fig 8A. Number of adherent cells counted in six randomly selected fields after incubation with anti-Gal-8 autoantibodies from three positive (MS10, MS14 and MS20) and three negative patients (MS 21, MS 18 and MS27). Anti-Gal-8 autoantibodies inhibit cell adhesion. (PDF)

Raw data of Fig 8B. In vitro differentiated Th17 cells from IL-17A-GFP reporter mice were purified based on IL-17A expression (GFP+) and incubated with Gal-8 (20 μg/ml) in the presence of lactose, sucrose or anti-Gal-8 antibodies affinity purified from pooled serum of MS patients. Numbers are the frequency of Annexin V+ 7AAD+ cells of the treated s...

Raw data of Fig 3: Frequencies of Th1 and Th17 subpopulations in splenocytes from 10 day-induced EAE Lgals8-/- (KO) and Lgals8+/+ (WT) mice re-stimulated for 72 h with MOGp in the absence (UN) or presence of Gal-8. (PDF)

Baseline characteristics of RRMS patients with and without anti-Gal-8 autoantibodies. RRMS patients before starting the DMD treatment, with or without Gal-8 autoantibodies in sera, share similar characteristics of age, gender, age at onset, disease duration, EDSS, and presence of baseline gadolinium-enhanced T1 lesions. (PDF)

Raw data of Patients. Clinical characteristic of 17 RRMS patients anti-Gal-8(+) and 19 RRMS patients anti-Gal-8(-): N (number of patient); Gender (1 is man and 0 is woman); Age (is age at Anti-Gal-8 assay in years); Age at onset MS (age at first symptoms in years); Diagnostic delay (time between age of onset and age of MS diagnosis); Disease durati...

JMJD3 a demethylase of lysine 27 of histone H3 (H3K27) plays an important role in immune cells and inflammatory responses, and thus appears as an attractive target for the treatment of inflammatory diseases. Recently, GSK-J4, a selective and potent JMJD3 inhibitor was synthesized. We previously showed that GSK-J4 induced a tolerogenic phenotype on...

Neuroinflammation involves the activation of glial cells, which is associated to the progression of neurodegeneration in Parkinson's disease. Recently, we and other researchers demonstrated that dopamine receptor D3 (D3R)-deficient mice are completely refractory to neuroinflammation and consequent neurodegeneration associated to the acute intoxicat...

APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G; A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4+ T cells are highly permissive for HIV-1 replication, whereas resting CD4+ T cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory...

As it has been established that demethylation of lysine 27 of histone H3 by the lysine-specific demethylase JMJD3 increases immune responses and thus elicits inflammation, we hypothesize that inhibition of JMJD3 may attenuate autoimmune disorders. We found that in vivo administration of GSK-J4, a selective inhibitor of JMJD3 and UTX, ameliorates th...

T helper type 17 (Th17) lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown...

Th17 cells delay effector T cell proliferation in a contact-dependent manner. Proliferation of effector CD4+ T cells during in vitro suppression assays with Th17TGF-β1 or Th17IL-23 cells. Th17TGF-β1 or Th17IL-23 cells were sorted based on IL-17-GFP expression and co-cultured for 3 days at different ratios with Violet-labeled CD4+ effector T cells f...

Th17TGF-β1 and Th17IL-23 subsets present similar in vivo persistence. 1.3x106 IL-17-GFP+ Th17TGF-β1 and Th17IL-23 cells were transferred to Rag1-/- mice and the percentage of CD4+ CD3+ was analyzed 8 weeks after adoptive transfer in the spleen (A), mesenteric lymph node (B) and small intestine lamina propria (C) (n = 6–7 mice per group). Data are p...

Dopamine receptor D3 (DRD3) expressed on CD4+ T cells is required to promote neuroinflammation in a murine model of Parkinson's disease. However, how DRD3 signaling affects T cell-mediated immunity remains unknown. In this study, we report that TCR stimulation on mouse CD4+ T cells induces DRD3 expression, regardless of the lineage specification. I...

APOBEC3G (A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4(+) T-cells are highly permissive for HIV-1 replication, while resting CD4(+) T-cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory. We investigated whether these differences could be related to a...

Neuroinflammation constitutes a fundamental process involved in the physiopathology of Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4+ T-cells infiltrate the central nervous system...

Dopamine receptors have been described in T-cells, however their signalling pathways coupled remain unknown. Since cAMP and ERKs play key roles regulating T-cell physiology, we aim to determine whether cAMP and ERK1/2-phosphorylation are modulated by dopamine receptor 3 (D3R) and D5R, and how this modulation affects CD4(+) T-cell activation and dif...

Neuroinflammation is involved in several neurodegenerative disorders and emerging evidence indicates that it constitutes a critical process that is required for the progression of neurodegeneration. Microglial activation constitutes a central event in neuroinflammation. Furthermore, microglia can not only be activated with an inflammatory and neuro...

Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuroimmune communications mediated by dopamine. Studies of dendritic cell...

Emerging evidence has demonstrated that CD4(+) T cells infiltrate into the substantia nigra (SN) in Parkinson's disease (PD) patients and in animal models of PD. SN-infiltrated CD4(+) T cells bearing inflammatory phenotypes promote microglial activation and strongly contribute to neurodegeneration of dopaminergic neurons. Importantly, altered expre...