Browsing by Subject "Adrenergic alpha-Agonists"
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Item Modulation of CD8+ T Cell Function by Beta2-Adrenergic Receptor Signaling(2017-05-31) Estrada, Leonardo Daniel; Malter, James; Farrar, J. David; Pfeiffer, Julie K.; Stowe, Ann; D'Orso, IvánThere is intimate crosstalk between the nervous system and the immune system. The nervous system can respond to immune system cues through afferent nerve endings. One effect of this response is the secretion of neurotransmitters in peripheral organs through efferent nerve endings. Primary and secondary immune organs are innervated predominantly by sympathetic nerve endings. The nerve termini are adrenergic and secrete norepinephrine upon stimulation, which can modulate immune cell function primarily through the beta2-adrenergic receptor (ADRB2). Our previous work has demonstrated that various subsets of CD8+ T cells have differential expression of the ADRB2 transcript. The role of ADRB2 signaling on the differentiation and acute effector functions of CD8+ T cells remains poorly understood. More importantly, its effect on CD8+ T cell memory development remains elusive. Therefore, I comprehensively addressed the role of ADRB2 signaling on different aspects of CD8+ T cell function. In the current body of work I demonstrate that intrinsic ADRB2 signaling downregulates CD8+ T cell acute effector functions, without affecting differentiation into effector cells. This is true with various forms of T cell receptor activation and with endogenous as well as pharmacological ADRB2 ligands. Furthermore, CD8+ T cell interferon-gamma secretion induced by innate cytokines was not affected. Finally, ADRB2-deficient CD8+ T cells fail to develop into memory cells after an in vivo viral infection. This effect is intrinsic to the ability of CD8+ T cells to signal through the ADRB2 as shown by bone marrow chimera experiments. The inability of ADRB2-deficient CD8+ T cells to develop into memory cells is accompanied by higher expression of several activation-related genes, as well as decreased expression of CD25 five days post-infection. However, restoration of CD25 expression in ADRB2-deficient cells with IL-2/anti-IL-2 treatment was unable to rescue memory development. Taken together, my results demonstrate for the first time that the sympathetic nervous system controls CD8+ T cell memory development through ADRB2 signaling on CD8+ T cells.Item Sympathetic Neural Control of Inflammation by ADRB2-Mediated IL-10 Secretion(2018-04-16) Agac, Didem; Hooper, Lora V.; Farrar, J. David; Gill, Michelle A.; Shiloh, MichaelThe nervous and immune systems reciprocally regulate their functions through the release of chemical messengers. Norepinephrine (NE), a neurotransmitter released by catecholaminergic nerve endings, allows the sympathetic nervous system to communicate with immune cells through adrenergic receptors (ADR). Although, the effects of adrenergic signaling has been studied in multiple cell types, its role in modulation of innate immune cells is relatively unknown. Here, I demonstrate a novel role for the beta2-ADR (ADRB2) in controlling inflammation. NE suppresses pro-inflammatory cytokine secretion from primary macrophages in response to multiple TLR agonists, and ADRB2 signaling enhances early induction of IL-10. In addition to its in vitro affects, I have shown that ADRB2 signaling controls inflammation in vivo. The in vivo role of this pathway was assessed by using an infection model, experimental colitis and LPS endotoxemia model. ADRB2-/- animals presented with splenomegaly and greater weight loss in infection and colitis, compared to ADRB2 sufficient animals, respectively. ADRB2-/- animals rapidly succumbed to a sub-lethal LPS challenge, which correlated with elevated serum levels of TNFα and reduced IL-10. Administration of exogenous IL-10 increased the survival of the ADRB2-/-. Additionally, the ADRB2-specific agonist salmeterol rescued wild-type animals from a lethal LPS challenge, which was reversed by neutralizing anti-IL-10 antibody. These observations suggest that ADRB2 signaling is critical for controlling inflammation through the rapid induction of IL-10. Transcriptome analysis revealed that the NR4A nuclear orphan family members were induced by NE. The presence of several putative NR4A binding sites within the IL-10 promoter suggests that these factors may directly regulate IL-10 expression in response to ADRB2 signaling. Additionally, mice that deficient in NR4A1 are susceptible in LPS endotoxemia model. These results suggest a novel pathway for control of inflammation via neuroendocrine cues. Understanding this pathway will provide new insights into how the nervous and immune systems communicate through ADRB2 signaling.