Dianne Lorton

Autonomic regulation of cellular immune function.

The nervous system and the immune system (IS) are two integrative systems that work together to detect threats and provide host defense, and to maintain/restore homeostasis. Cross-talk between the nervous system and the IS is vital for health and well-being. One of the major neural pathways responsible for regulating host defense against injury and foreign antigens and pathogens is the sympathetic nervous system (SNS). Stimulation of adrenergic receptors (ARs) on immune cells regulates immune cell development, survival, proliferative capacity, circulation, trafficking for immune surveillance and recruitment, and directs the cell surface expression of molecules and cytokine production important for cell-to-cell interactions necessary for a coordinated immune response. Finally, AR stimulation of effector immune cells regulates the activational state of immune cells and modulates their functional capacity. This review focuses on our current understanding of the role of the SNS in regulating host defense and immune homeostasis. SNS regulation of IS functioning is a critical link to the development and exacerbation of chronic immune-mediated diseases. However, there are many mechanisms that need to be further unraveled in order to develop sound treatment strategies that act on neural-immune interaction to resolve or prevent chronic inflammatory diseases, and to improve health and quality of life.

Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells.

Adjuvant-induced arthritis induces c-Fos chronically in neurons in the hippocampus

Chronic pain, sickness behaviors, and cognitive decline are symptoms in rheumatoid arthritis. In the adjuvant-induced arthritis Lewis rat model, we examined the dynamics of c-Fos expression in the hippocampus, a brain region important for these symptoms. Brain sections were stained for c-Fos using immunohistochemistry. c-Fos-positive nuclei were counted in CA1, CA2, CA3 and the dentate gyrus of the dorsal hippocampi from rats receiving no treatment or base-of-the-tail injections of (1 or 2) incomplete or complete Freunds adjuvant (low- or high-dose), (3), Mycobacterium butyricum cell wall suspended in saline, or (4) saline, and sacrificed 4, 14, 21, or 126days post-immunization. Disease severity was evaluated by dorsoplantar foot pad widths and X-ray analysis. We report sustained dose- and subfield-dependent c-Fos expression with arthritis, but transient expression in nonarthritic groups, suggesting long-term genomic changes in rheumatoid arthritis that may be causal for behavioral changes, adaptation to chronic pain and/or cognitive decline associated with disease.

Targeting α- and β-Adrenergic Receptors Differentially Shifts Th1, Th2, and Inflammatory Cytokine Profiles in Immune Organs to Attenuate Adjuvant Arthritis

The sympathetic nervous system (SNS) regulates host defense responses and restores homeostasis. SNS-immune regulation is altered in rheumatoid arthritis (RA) and rodent models of RA, characterized by nerve remodeling in immune organs and defective adrenergic receptor (AR) signaling to immune cell targets. The SNS typically promotes or suppresses inflammation via α- and β2-AR activation, respectively, and indirectly drives humoral immunity by blocking Th1 cytokine secretion. Here, we investigate how β2-AR stimulation and/or α-AR blockade at disease onset affects disease pathology and cytokine profiles in relevant immune organs from male Lewis rats with adjuvant-induced arthritis (AA). Rats challenged to induce AA were treated with terbutaline (TERB), a β2-AR agonist (600u2009μg/kg/day) and/or phentolamine (PHEN), an α-AR antagonist (5.0u2009mg/kg/day) or vehicle from disease onset through severe disease. We report that in spleen, mesenteric (MLN) and draining lymph node (DLN) cells, TERB reduces proliferation, an effect independent of IL-2. TERB also fails to shift T helper (Th) cytokines from a Th1 to Th2 profile in spleen and MLN (no effect on IFN-γ) and DLN (greater IFN-γ) cells. In splenocytes, TERB, PHEN, and co-treatment (PT) promotes an anti-inflammatory profile (greater IL-10) and lowers TNF-α (PT only). In DLN cells, drug treatments do not affect inflammatory profiles, except PT, which raised IL-10. In MLN cells, TERB or PHEN lowers MLN cell secretion of TNF-α or IL-10, respectively. Collectively, our findings indicate disrupted β2-AR, but not α-AR signaling in AA. Aberrant β2-AR signaling consequently derails the sympathetic regulation of lymphocyte expansion, Th cell differentiation, and inflammation in the spleen, DLNs and MLs that is required for immune system homeostasis. Importantly, this study provides potential mechanisms through which reestablished balance between α- and β2-AR function in the immune system ameliorates inflammation and joint destruction in AA.

Characterization of fibromyalgia symptoms in patients 55–95 years old: a longitudinal study showing symptom persistence with suboptimal treatment

BackgroundFibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption.AimsTo characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms.MethodsA longitudinal, observational study of 51 subjects with FM (range 55–95xa0years) and 81 control subjects (58–95xa0years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment.ResultsPain and stiffness that interfered with physical activity, sleep, and mood were reported by 80xa0% or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin.DiscussionIn this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated.ConclusionsAge-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.

Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy

AbstractRosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects.n Funding: Galderma International S.A.S., Paris, France.

Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis

Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side effects. The discovery of new, effective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5xa0mg/kg/day, in 500xa0μl sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (~70%) and bone loss (~50%) compared with AA controls. SNS treatment also reduced spleen weight (without affecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered T-helper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our findings support the development of SNS as a therapeutic for RA.

Chronically lowering sympathetic activity protects sympathetic nerves in spleens from aging F344 rats.

In the present study, we investigated how increased sympathetic tone during middle-age affects the splenic sympathetic neurotransmission. Fifteen-month-old (M) F344 rats received rilmenidine (0, 0.5 or 1.5mg/kg/day, i.p. for 90 days) to lower sympathetic tone. Controls for age were untreated 3 or 18M rats. We report that rilmenidine (1) reduced plasma and splenic norepinephrine concentrations and splenic norepinephrine turnover, and partially reversed the sympathetic nerve loss; and (2) increased β-adrenergic receptor (β-AR) density and β-AR-stimulated cAMP production. Collectively, these findings suggest a protective effect of lowering sympathetic tone on sympathetic nerve integrity, and enhanced sympathetic neurotransmission in secondary immune organs.

Central sympathetic inhibition ameliorates joint pathology and shifts cytokines profiles in spleen but not joint draining lymph nodes in a model of rheumatoid arthritis

In 80% of patients, major life stressors precede onset of autoimmune diseases, including rheumatoid arthritis (RA) linking stress pathway activation to disease onset. We examined the contribution of high sympathetic nervous system activity to RA onset using the adjuvant-induced (AA) arthritis model in Lewis rats. Rats were immunized with complete Freund’s adjuvant to induce AA. From day (D)12 (disease onset) through D28, rats were treated with vehicle or 2xa0mg/kg/day moxonidine, an imidazoline receptor-1 agonist that acts centrally to reduce SNS tone. Disease outcome was assessed using dorsoplantar widths and X-ray analysis. Cytokines critical for inflammation and CD4+ Th cell development (interleukin (IL)-1 β , IL-10, tumor necrosis factor (TNF)- α , IL-6, IL-2, IL-4, IFN- γ , and tumor growth factor (TGF)- β ) were assessed in spleen, draining lymph node (DLN) and peripheral blood mononuclear cells (PBMCs) by enzyme-linked immunoassays. Treatment with moxonidine dramatically prevented hind foot inflammation and joint destruction in AA compared with vehicle treatment. In DLN cells, moxonidine treatment had no effect on cytokine production. In contrast, moxonidine treatment significantly reduced IL-1 β , IL-2, IL-4 and IFN- γ in PBMCs. Drug treatment decreased splenocyte production of TGF- β and IFN- γ by ∼ 50% and ∼ 30%, respectively. Lowering SNS tone effectively reduced clinical signs of disease and altered production of cytokines involved in inflammation and shifting the balance between auto-reactive CD4+Th cells and T regulatory cells in directions expected to limit disease activity.

115. “Inflammaging” and psychosocial stress in a murine orthotopic prostate cancer model

Prostate cancer (PCa) is prevalent in older men, and the second leading cause of mortality. Aging and psychosocial stress affect tumor progression in other reproductive cancers, but interactions between age, stress and tumor progression in PCa remain unexplored. Since inflammation is a key player in tumor progression, we evaluated the effects of age and psychosocial stress on pro- and anti-inflammatory mediators in an orthotopic PCa model. Young (2xa0M) or old (18xa0M) male C57BL/6 mice with orthotopic RM-9 tumors were subjected to 14xa0days of combined social isolation and 2-h restraint (stressed) or remained group-housed in home cages (nonstressed). Twenty-five cytokines were quantified in tumor homogenates using multiplexed ELISAs. Age effects were evident for six proinflammatory cytokines ( p p