Accurate differential analysis of transcription factor activity from gene expression.

MOTIVATION: Activity of transcriptional regulators is crucial in elucidating the mechanism of phenotypes. However regulatory activity hypotheses are difficult to experimentally test. Therefore, we need accurate and reliable computational methods for regulator activity inference. There is extensive work in this area, however, current methods have difficulty with one or more of the following: resolving activity of TFs with overlapping regulons, reflecting known regulatory relationships, or flexible modeling of TF activity over the regulon. RESULTS: We present Effector and Perturbation Estimation Engine (EPEE), a method for differential analysis of transcription factor (TF) activity from gene expression data. EPEE addresses each of these principal challenges in the field. Firstly, EPEE collectively models all TF activity in a single multivariate model, thereby accounting for the intrinsic coupling among TFs that share targets, which is highly frequent. Secondly, EPEE incorporates context-specific TF-gene regulatory networks and therefore adapts the analysis to each biological context. Finally, EPEE can flexibly reflect different regulatory activity of a single TF among its potential targets. This allows the flexibility to implicitly recover other regulatory influences such as co-activators or repressors. We comparatively validated EPEE in 15 datasets from three well-studied contexts, namely immunology, cancer, and hematopoiesis. We show that addressing the aforementioned challenges enable EPEE to outperform alternative methods and reliably produce accurate results. AVAILABILITY AND IMPLEMENTATION: https://github.com/Cobanoglu-Lab/EPEE. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The ß2-adrenergic receptor controls inflammation by driving rapid IL-10 secretion.

The mammalian nervous system communicates important information about the environment to the immune system, but the underlying mechanisms are largely unknown. Secondary lymphoid organs are highly innervated by sympathetic neurons that secrete norepinephrine (NE) as the primary neurotransmitter. Immune cells express adrenergic receptors, enabling the sympathetic nervous system to directly control immune function. NE is a potent immunosuppressive factor and markedly inhibits TNF-α secretion from innate cells in response to lipopolysaccharide (LPS). In this study, we demonstrate that NE blocks the secretion of a variety of proinflammatory cytokines by rapidly inducing IL-10 secretion from innate cells in response to multiple Toll-like receptor (TLR) signals. NE mediated these effects exclusively through the ß2-adrenergic receptor (ADRB2). Consequently, Adrb2-/- animals were more susceptible to L. monocytogenes infection and to intestinal inflammation in a dextran sodium sulfate (DSS) model of colitis. Further, Adrb2-/- animals rapidly succumbed to endotoxemia in response to a sub-lethal LPS challenge and exhibited elevated serum levels of TNF-α and reduced IL-10. LPS-mediated lethality in WT animals was rescued by administering a ß 2-specific agonist and in Adrb2-/- animals by exogenous IL-10. These findings reveal a critical role for ADRB2 signaling in controlling inflammation through the rapid induction of IL-10. Our findings provide a fundamental insight into how the sympathetic nervous system controls a critical facet of immune function through ADRB2 signaling.

Adrenergic Signaling at the Interface of Allergic Asthma and Viral Infections.

Upper respiratory viral infections are a major etiologic instigator of allergic asthma, and they drive severe exacerbations of allergic inflammation in the lower airways of asthma sufferers. Rhinovirus (RV), in particular, is the main viral instigator of these pathologies. Asthma exacerbations due to RV infections are the most frequent reasons for hospitalization and account for the majority of morbidity and mortality in asthma patients. In both critical care and disease control, long- and short-acting ß2-agonists are the first line of therapeutic intervention, which are used to restore airway function by promoting smooth muscle cell relaxation in bronchioles. While prophylactic use of ß2-agonists reduces the frequency and pathology of exacerbations, their role in modulating the inflammatory response is only now being appreciated. Adrenergic signaling is a component of the sympathetic nervous system, and the natural ligands, epinephrine and norepinephrine (NE), regulate a multitude of autonomic functions including regulation of both the innate and adaptive immune response. NE is the primary neurotransmitter released by post-ganglionic sympathetic neurons that innervate most all peripheral tissues including lung and secondary lymphoid organs. Thus, the adrenergic signaling pathways are in direct contact with both the central and peripheral immune compartments. We present a perspective on how the adrenergic signaling pathway controls immune function and how ß2-agonists may influence inflammation in the context of virus-induced asthma exacerbations.

Sympathetic neural signaling via the ß2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8(+) T-cell effector function.

Postganglionic sympathetic neurons innervate secondary lymphoid organs and secrete norepinephrine (NE) as the primary neurotransmitter. NE binds and signals through five distinct members of the adrenergic receptor family. In this study, we show elevated expression of the ß2-adrenergic receptor (ADRB2) on primary human CD8(+) effector memory T cells. Treatment of both human and murine CD8(+) T cells with NE decreased IFN-γ and TNF-α secretion and suppressed their cytolytic capacity in response to T-cell receptor (TCR) activation. The effects of NE were specifically reversed by ß2-specific antagonists. Adrb2(-/-) CD8(+) T cells were completely resistant to the effects of NE. Further, the ADRB2-specific pharmacological ligand, albuterol, significantly suppressed effector functions in both human and mouse CD8(+) T cells. While both TCR activation and stimulation with IL-12 + IL-18 were able to induce inflammatory cytokine secretion, NE failed to suppress IFN-γ secretion in response to IL-12 + IL18. Finally, the long-acting ADRB2-specific agonist, salmeterol, markedly reduced the cytokine secretion capacity of CD8(+) T cells in response to infection with vesicular stomatitis virus. This study reveals a novel intrinsic role for ADRB2 signaling in CD8(+) T-cell function and underscores the novel role this pathway plays in adaptive T-cell responses to infection.