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1.
Cell ; 164(3): 378-91, 2016 Jan 28.
Article in English | MEDLINE | ID: mdl-26777404

ABSTRACT

Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to ß2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.


Subject(s)
Intestine, Small/physiology , Macrophages/immunology , Neurons/cytology , Animals , Cell Line , Intestinal Mucosa/cytology , Intestinal Mucosa/physiology , Intestine, Small/cytology , Intestine, Small/immunology , Macrophages/cytology , Mice , Mucous Membrane/cytology , Mucous Membrane/physiology , Neuroimmunomodulation , Neurons/physiology , Receptors, Adrenergic, beta-2/metabolism , Salmonella Infections/immunology , Salmonella typhimurium/physiology , Specific Pathogen-Free Organisms
2.
Neuroimmunomodulation ; 17(3): 196-9, 2010.
Article in English | MEDLINE | ID: mdl-20134201

ABSTRACT

Stress has long been recognized as a putative modulator of immunity. Several clinical and experimental reports point to a role of physical and psychological stressors on progression or resistance to disease. Nonetheless, literature in this field is sometimes controversial due to the wide variety of stressors employed and parameters of immunity analyzed. This variation should not be considered a consequence of methodological inaccuracy. The stress response, although theoretically stereotyped in nature, may lead to slightly different outcomes according to several modifiers. Our group has compared the effects of several stressors over different parameters of brain activity, behavior, immunity and glucocorticoid levels. These data show altogether that while increased turnover of noradrenaline in the hypothalamus, along with anxiety-like behaviors and increase in serum corticosterone are present very often, the magnitude of changes in immunity may vary considerably. Thus, we review data from our group generated over the past decade to support that effects of stressors on immunity and behavior highly depend on their specifics, animal model, frequency, duration, intensity, perception, and coping by the stressed animal.


Subject(s)
Hypothalamo-Hypophyseal System/immunology , Neuroimmunomodulation/physiology , Pituitary-Adrenal System/immunology , Stress, Psychological/immunology , Stress, Psychological/physiopathology , Animals , Anxiety/immunology , Anxiety/metabolism , Anxiety/physiopathology , Corticosterone/metabolism , Disease Models, Animal , Humans , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Immune Tolerance/physiology , Mice , Norepinephrine/metabolism , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/physiopathology , Social Behavior
3.
Int Immunopharmacol ; 10(4): 431-9, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20093200

ABSTRACT

The endocannabinoid system has become a topic of great interest in pharmacology due to its remarkable distribution in mammal organisms and capacity to play a modulatory role on several physiological systems, including modulation of immunity. Many studies have shown that administration of cannabinoids causes inhibitory effects on immune cells, including decreased proliferation and antigen-presenting cell (APC) co-stimulatory activity. In contrast, other groups have shown that some cannabinoids might present stimulatory actions on macrophage activity and T cell activation. Therefore, we aimed to investigate whether a treatment in vivo with a low dose of anandamide (0.1mg/kg) immediately prior to sensitization would have an immunosuppressive or immunostimulatory effect on cell-mediated immunity (Th1 response) in mice. We report here that anandamide, prior to sensitization, was able to increase the Th1 response to ovalbumin in vivo and ex vivo. Anandamide increased delayed type hypersensitivity (DTH), splenocyte proliferation, and IFN-gamma production in a co-culture of adherent and non-adherent splenocytes. Moreover, anandamide prior to sensitization increased both the expression of DC co-stimulatory molecules (CD80/CD86) and IL-12/IL23 (p40) production ex vivo. We have also assessed direct effects of anandamide in the IFN-gamma/IL-4 balance of ConA-stimulated splenocytes in vitro. Anandamide at nanomolar concentrations increased the production of IFN-gamma, while such production decreased at micromolar range. Thus, anandamide induced both the increment of DC activation and IFN-gamma production, which are likely the mechanisms involved in the increase of Th1 response reported here.


Subject(s)
Adjuvants, Immunologic/pharmacology , Arachidonic Acids/pharmacology , Immunity, Cellular/drug effects , Polyunsaturated Alkamides/pharmacology , Animals , Anxiety/psychology , Cell Proliferation/drug effects , Corticosterone/blood , Cytokines/biosynthesis , Dendritic Cells/drug effects , Dendritic Cells/immunology , Endocannabinoids , Enzyme-Linked Immunosorbent Assay , Exploratory Behavior/drug effects , Hypersensitivity, Delayed/immunology , Hypothalamo-Hypophyseal System/drug effects , Interferon-gamma/biosynthesis , Interleukin-4/biosynthesis , Macrophages/drug effects , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Th1 Cells/drug effects , Th1 Cells/immunology
4.
Neuroimmunomodulation ; 16(1): 19-27, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19077442

ABSTRACT

BACKGROUND: Mice allergic to ovalbumin (OVA) avoid drinking a solution containing this antigen. This was interpreted as related to IgE-dependent mast cell degranulation and sensory C fiber activation. METHODS: We employed pharmacological manipulation to further investigate the mediators involved in immune-induced food aversion. RESULTS: While nonimmunized rats preferred a sweetened OVA solution, immunized rats avoided it. We also employed a paradigm in which rats are conditioned to drink water for two 10-min sessions a day. Tolerant rats presented lower IgE titers, and this manipulation abrogated food aversion. Dexamethasone (1.0 mg/kg) prevented the aversion of OVA-immunized rats to the antigen-containing solution. Combined blockade of H(1) and 5-hydroxytryptamine (5-HT)(2) receptors by promethazine (3.0 mg/kg) plus methysergide (5.0 mg/kg) was unable to alter food aversion. Blockade of 5-HT(3) receptors by ondansetron (1.0 mg/kg) caused a twofold increase in the ingestion of the sweetened OVA solution by immunized rats, suggesting the involvement of 5-HT(3) receptors in food aversion. Finally, we showed that dexamethasone or promethazine plus methysergide, but not ondansetron, effectively prevented the IgE-dependent mast-cell-degranulation-induced increase in vascular permeability in rats. CONCLUSION: We suggest that regardless of whether or not they cause edema, IgE-mediated mast cell degranulation and consequent 5-HT(3) signaling are involved in the process that triggers avoidance to the source of the allergen in allergic rats.


Subject(s)
Feeding Behavior , Food Hypersensitivity/immunology , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Capillary Permeability/drug effects , Capillary Permeability/immunology , Cell Degranulation/drug effects , Cell Degranulation/immunology , Conditioning, Psychological/physiology , Dexamethasone/pharmacology , Disease Models, Animal , Food Hypersensitivity/physiopathology , Immunoglobulin E/blood , Immunoglobulin E/immunology , Immunosuppressive Agents/pharmacology , Male , Mast Cells/drug effects , Mast Cells/immunology , Methysergide/pharmacology , Ondansetron/pharmacology , Ovalbumin/immunology , Rats , Rats, Wistar , Serotonin/metabolism , Serotonin 5-HT3 Receptor Antagonists , Serotonin Antagonists/pharmacology
5.
J Clin Invest ; 118(4): 1532-43, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18340379

ABSTRACT

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75-treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75-treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.


Subject(s)
Axons/pathology , Multiple Sclerosis/pathology , Amino Acid Transport System X-AG/metabolism , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Axons/drug effects , Axons/metabolism , B-Lymphocytes/drug effects , CD11b Antigen/metabolism , Chemokine CCL2/metabolism , Chronic Disease , Disease Models, Animal , Disease Progression , Fullerenes/chemistry , Fullerenes/therapeutic use , Glutamic Acid/pharmacology , Memory/drug effects , Mice , Molecular Structure , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Oxidative Stress/drug effects , T-Lymphocytes/drug effects
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