Biology subjects

Reed, E. C.

Publications and source records attributed to Reed, E. C..

4 recordsLinked to original sources

bioRxiv2025

Beta Adrenergic Signaling as a Therapeutic Target for Autoimmunity

BackgroundWe recently identified a molecular mechanism involving beta-adrenergic 1 and 2 receptors ({beta}1/2) in the development of TH17 lymphocytes. Pharmacological and genetic inhibition of these receptors in combination, but not separately, impaired the ability of T-lymphocytes to produce proinflammatory interleukin 17A (IL-17A) and instead promoted the production of protective Treg cells that secrete anti-inflammatory interleukin-10 (IL-10). However, it remained unclear whether this regulatory mechanism could serve as a novel therapeutic approach for autoimmune disorders mediated by IL-17A-producing T-lymphocytes. MethodsMultiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS) characterized by an autoimmune response where both T-lymphocytes and IL-17A are implicated in the pathogenesis of the disease. Using an animal model of MS, termed experimental autoimmune encephalomyelitis (EAE), we addressed the impact of beta adrenergic receptor blockade (genetically and pharmacologically) on EAE disease progression, severity, and TH17/Treg balance. ResultsThe genetic deletion {beta}1/2 receptors, either systemically or specifically in T-lymphocytes, significantly attenuated EAE disease severity and animal weight loss. Pharmacological blockade of {beta}1/2 receptors with either propranolol (lipophilic) or nadolol (aqueous) limited disease severity and weight loss similar to the genetic models. All models showed degrees of shifted TH17/Treg balance (suppressing TH17 and promoting Treg) and decreased T-lymphocyte IL-17A production. Importantly, pharmacological blockade was initiated at the time of symptom development, which mimics the typical time where diagnosis of disease would occur. ConclusionsOur data depict a novel role for {beta}1/2 adrenergic signaling in the control of TH17/Treg cells in EAE. These findings provide new insight into the disease progression as well as provide a potential new pharmacological therapy for IL-17A-related autoimmune diseases.

immunology↗

bioRxiv2024

Hemoglobin alpha is a redox-sensitive mitochondrial-related protein in T-lymphocytes

AbstractHemoglobin subunits, which form the well-characterized, tetrameric, oxygen-carrying protein, have recently been described to be expressed in various non-canonical cell types. However, the exact function of hemoglobin subunits within these cells remains to be fully elucidated. Herein, we report for the first time, the expression of hemoglobin alpha-a1 (Hba-a1) in T-lymphocytes and describe its role as a mitochondrial- associated antioxidant. Within naive T-lymphocytes, Hba-a1 mRNA and HBA protein are present and highly induced by redox perturbations, particularly those arising from the mitochondria. Additionally, preliminary data using a T-lymphocyte specific Hba-a1 knock-out mouse model indicated that the loss of Hba-a1 led to an exacerbated production of mitochondrial reactive oxygen species and inflammatory cytokines after a stress challenge, further supporting the role of HBA acting to buffer the mitochondrial redox environment. Interestingly, we observed Hba-a1 expression to be significantly upregulated or downregulated depending on T-lymphocyte polarization and metabolic state, which appeared to be controlled by both transcriptional regulation and chromatin remodeling. Altogether, these data suggest Hba-a1 may function as a crucial mitochondrial-associated antioxidant and appears to possess critical and complex functions related to T- lymphocyte activation and differentiation.

immunology↗

bioRxiv2024

Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis

BackgroundPost-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a preclinical model of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear. MethodsUsing a modified version of repeated social defeat stress (RSDS) that allows for both males and females, we assessed the impact of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte IL-17A generation. Additionally, we explored the impact of adrenergic signaling and T-lymphocyte-produced catecholamines on both CD4+ and CD8+ T-lymphocytes polarized to IL-17A-producing phenotypes ex vivo. ResultsOnly pharmacological inhibition of the beta 1 and 2 adrenergic receptors ({beta}1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g., IL-6, TNF-, and IL-10). This finding was confirmed using RSDS with both global {beta}1/2 receptor knock-out mice, as well as by adoptively transferring {beta}1/2 knock-out T-lymphocytes into immunodeficient hosts. Furthermore, ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of {beta}1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Indeed, pharmacological depletion of catecholamines both in vivo and ex vivo abrogated T-lymphocyte IL-17A production demonstrating the importance of immune-generated neurotransmission in pro-inflammatory cytokine generation. ConclusionsOur data depict a novel role for {beta}1/2 adrenergic receptors and autologous catecholamine signaling during T-lymphocyte IL-17A production. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.

immunology↗

bioRxiv2022

S100a9 Attenuates Inflammation during Repeated Social Defeat Stress

Post-traumatic stress disorder (PTSD), a consequence of psychological trauma, is associated with increased inflammation and an elevated risk of developing comorbid inflammatory diseases. However, the mechanistic link between this mental health disorder and inflammation remains elusive. Using a pre-clinical model of PTSD known as repeated social defeat stress (RSDS), we previously identified that S100a8 and S100a9 mRNA, genes that encode the protein calprotectin, were significantly upregulated in T-lymphocytes after psychological trauma. Calprotectin expression positively correlated with inflammatory gene expression and the mitochondrial redox environment in T-lymphocytes, therefore, we hypothesized that genetic deletion of calprotectin would attenuate the inflammatory and redox phenotype displayed after RSDS. Using pharmacological and genetic manipulation of S100a9 (which functionally eliminates calprotectin) in mice, we unexpectedly observed worsening of behavioral pathology, inflammation, and the mitochondrial redox environment in mice after RSDS compared to wild-type (WT) animals. Furthermore, loss of calprotectin significantly enhanced the metabolic demand on T-lymphocytes suggesting this protein may play an undescribed role in mitochondrial regulation. This was further supported by single-cell RNA sequencing analysis demonstrating that RSDS and loss of S100a9 primarily altered genes associated with mitochondrial function and oxidative phosphorylation. Taken together, these data demonstrate the loss of calprotectin potentiates the RSDS-induced phenotype, which suggests its observed upregulation after psychological trauma may provide previously unexplored protective functions.

immunology↗