Biology subjects

Case, A. J.

Publications and source records attributed to Case, A. J..

11 recordsLinked to original sources

bioRxiv2026

Norepinephrine is a novel and essential regulator for T-lymphocyte interleukin 17A expression

The longstanding association between psychological trauma or stress and subsequent chronic inflammatory disorders is well-documented, but the mechanism by which psychopathology causes these immune changes has yet to be elucidated. We have previously reported that sympathetic innervation to lymphoid organs and beta adrenergic receptor signaling are essential for T-lymphocyte interleukin 17A (IL-17A) production and TH17 polarization, though the exact mechanistic contribution of this signaling to the development of TH17 cells remained unclear. Therefore, we hypothesized that norepinephrine (NE) is a novel and direct regulator of T-lymphocyte IL-17A expression. Herein, we indeed observed that NE regulates baseline IL-17A in vivo. We further identified a novel mechanism by which transforming growth factor beta (TGF{beta}) and NE together result in TH17 polarization and IL-17A production in CD4+ T-lymphocytes. Additionally, we found that cAMP, PKA, and CREB are induced by NE signaling, which ultimately increases CBP/p300 activity to initiate ROR{gamma}t transcription. Surprisingly, our data also demonstrate that STAT3, a transcription factor previously described as necessary for canonical TH17 polarization, is not involved in this novel pathway and may even be downregulated. Combined with bulk RNA sequencing data, our data highlight robust differences between the novel and canonical pathways to TH17 polarization. Altogether, our data reveal a novel, noncanonical mechanism that links sympathetic nervous system activity with IL-17A related inflammation, which may have significant relevance to sympathoexcitation-related disorders that stem from psychological trauma or stress.

immunology↗

bioRxiv2026

Gene-drug interactions identify genomic loci that enhance statin effectiveness in lowering LDL cholesterol.

Hyperlipidemia, and high low-density lipoprotein cholesterol (LDL-c) in particular, is a risk factor for cardiovascular disease, including atherosclerosis, myocardial infarction, and stroke. Nearly 200 million people worldwide take HMG-CoA reductase inhibitors, commonly known as statins, to lower their LDL-c. If statins interfere with the genetic pathways that endogenously increase the risk for hyperlipidemia, gene-statin interactions may identify genomic variants, and thereby individuals with those genotypes, that are particularly sensitive to these medications. We performed a series of genome-wide gene-statin interaction analyses in the UK Biobank for LDL-c and two related lipids: high-density lipoprotein cholesterol (HDL-c) and triglycerides (TG). We identified five genome-wide significant gene-statin interactions for LDL-c, two interactions for HDL-c, and four interactions for TG. Importantly, only the SNP-based heritability of LDL-c was reduced by statin use. Using data from All of Us, we replicated all five significant gene-statin interaction loci for LDL-c in the European-like ancestry sample, two loci in the Americas-like ancestry sample, and one locus in the African-like ancestry sample. We also identified fifteen loci that remained associated with LDL-c despite statin treatment, highlighting potential additional genetic targets for drug development, enhancement, and repurposing. These loci include gene-targets for the recently developed hyperlipidemia drug class (PCSK9 inhibitors) validating our approach to finding new treatments. These results are an important step towards personalized medicine for patients with hyperlipidemia. Author SummaryHigh cholesterol raises the risk of heart attacks and strokes and nearly 200 million people worldwide take statins to lower it. While statins work for nearly everyone, they work better for some people than others. We examined how genetic differences enhance the effectiveness of statin medication as a step toward enhancing personalized medicine for those with high cholesterol. By analyzing genetic and health data from about 390,000 people, we found that statins primarily disrupt the link between genes and LDL or "bad" cholesterol levels. Across the genome, statins reduce the impact of genes on LDL-c levels, but not other blood lipids like HDL-c or triglycerides. For LDL-c specifically, we found five regions where genetic differences increase the effectiveness of statins. People with the protective genetic variants are expected to see greater cholesterol reduction with statin use. We confirmed four of the five findings in European-like ancestry samples, with partial replication in Americas-like and African-like ancestry samples (two variants and one variant, respectively). We also found 15 genomic regions where cholesterol stays high despite statin treatment. These genomic regions could be targets for new or enhanced cholesterol medications. In fact, a newer drug class targets one of these regions supporting our approach to finding new treatments.

genetics↗

bioRxiv2025

Psychological trauma increases blood pressure sensitivity to angiotensin II via T-lymphocytes independent of psychopathology

Exposure to traumatic stress can lead to psychopathology, including post-traumatic stress disorder (PTSD), but may also cause inflammation and cardiovascular dysfunction. Clinical evidence suggests that exposure to traumatic stress, independent of psychopathology development, may be sufficient to induce pathophysiological sequelae, but this has not been thoroughly investigated. Using a model of repeated social defeat stress (RSDS), we explored links between the behavioral and physiological consequences of this paradigm. RSDS was sufficiently able to elevate systemic inflammation in both male and female mice, with no observed sex differences. RSDS also induced a heightened blood pressure sensitization response to low dose exogenous angiotensin II (AngII), suggesting the model was also sufficient in generating cardiovascular pathology. Interestingly, the RSDS-induced sensitization to AngII was completely abrogated in mice lacking T-lymphocytes (i.e., Rag2-/- mice). Of note, Rag2-/- mice demonstrated similar pro-social and anxiety-like behavior to wild-type mice, inferring that 1) differences in these behavioral outcomes do not explain the loss of RSDS-induced AngII sensitization in Rag2-/- mice and 2) T-lymphocytes do not appear to impact these specific RSDS-induced behaviors. Indeed, intra-animal correlations demonstrate a tight association between the inflammatory and cardiovascular consequences post-RSDS, but no associations between these parameters with behavior. Together, our data suggest that exposure to traumatic stress, independent of psychopathology, is sufficient to induce pathophysiology. These findings have significant clinical implications, specifically for individuals who have experienced traumatic stress without the development of psychopathology, as this overlooked population may have similar risks of developing somatic diseases.

animal behavior and cognition↗

bioRxiv2025

Hemoglobin alpha regulates T-lymphocyte activation and mitochondrial function

We have recently discovered hemoglobin alpha a1 (Hb-a1 mRNA and Hb protein) in T-lymphocytes and previously reported that its expression was sensitive to mitochondrial redox perturbations. However, outside of its occurrence and basic characterization, the functional role of Hb in T-lymphocytes remained unknown. Herein, we identify Hb in both CD4+ and CD8+ T-lymphocyte subsets, and found its expression is highly dynamic, differs between the two subtypes, and is dependent upon activation stage. Further, the loss of Hb by use of a novel T-lymphocyte-specific Hb knock-out mouse impairs mitochondrial function, dysregulates cytokine production, and lowers the activation threshold primarily in CD4+ T-lymphocytes, indicating a critical role for Hb within this subset. While these data suggested the loss of Hb in T-lymphocytes may promote aberrant activation of autoreactive T-lymphocytes, surprisingly, we discovered that mice lacking Hb in T-lymphocytes exhibited reduced severity of experimental autoimmune encephalomyelitis (EAE) compared to wild-type control animals. Interestingly, T-lymphocytes lacking Hb in vivo appeared to function identically to wild-type controls, which did not explain the protection against EAE. In contrast, T-lymphocyte Hb knock-out mice displayed significantly reduced levels of circulating immunoglobulins and CD40L expression compared to their wild-type counterparts during EAE, suggesting possible impaired intercellular communication. These data elucidate a previously unrecognized role for Hb in T-lymphocyte function, which may have implications for hemoglobin-related diseases (i.e., hemoglobinopathies).

immunology↗

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↗

bioRxiv2022

T-lymphocyte Tyrosine Hydroxylase Regulates TH 17 T-lymphocytes during Repeated Social Defeat Stress

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which results in deleterious changes to psychological and physical health. Patients with PTSD are especially susceptible to co-morbid inflammation-driven pathologies, such as autoimmunity, while also demonstrating increased T-helper 17 (TH17) lymphocyte-driven inflammation. While the exact mechanism of this increased inflammation is unknown, overactivity of the sympathetic nervous system is a hallmark of PTSD. Neurotransmitters of the sympathetic nervous system (i.e., catecholamines) can alter T-lymphocyte function, which we have previously demonstrated to be partially mitochondrial redox-mediated. Furthermore, we have previously elucidated that T-lymphocytes generate their own catecholamines, and strong associations exist between tyrosine hydroxylase (TH; the rate-limiting enzyme in the synthesis of catecholamines) and pro-inflammatory interleukin 17A (IL-17A) expression within purified T-lymphocytes in a preclinical rodent model of PTSD. Therefore, we hypothesized that T-lymphocyte-generated catecholamines drive TH17 T-lymphocyte polarization through a mitochondrial superoxide-dependent mechanism during psychological trauma. To test this, T-lymphocyte-specific TH knockout mice (THT-KO) were subjected to repeated social defeat stress (RSDS). RSDS characteristically increased tumor necrosis factor- (TNF), IL-6, IL-17A, and IL-22, however, IL-17A and IL-22 (TH17 produced cytokines) were selectively attenuated in circulation and in T-lymphocytes of THT-KO animals. When activated ex vivo, secretion of IL-17A and IL-22 by THT-KO T-lymphocytes was also found to be reduced, but could be partially rescued with supplementation of norepinephrine specifically. Interestingly, THT-KO T-lymphocytes were still able to polarize to TH17 under exogenous polarizing conditions. Last, contrary to our hypothesis, we found RSDS-exposed THT-KO T-lymphocytes still displayed elevated mitochondrial superoxide, suggesting increased mitochondrial superoxide is upstream of T-lymphocyte TH induction, activity, and TH17 regulation. Overall, these data demonstrate TH in T-lymphocytes plays a critical role in RSDS-induced TH17 T-lymphocytes and offer a previously undescribed regulator of inflammation in RSDS.

immunology↗

bioRxiv2021

Splenic denervation attenuates repeated social defeat stress-induced T-lymphocyte inflammation

BackgroundPost-traumatic stress disorder (PTSD) is a devastating psychological disorder that significantly increases the risk for inflammatory diseases. While the exact etiology of this predisposition remains unclear, PTSD canonically increases overall sympathetic tone resulting in increased norepinephrine (NE) outflow. Previously, we demonstrated that exogenous NE alters mitochondrial superoxide in T-lymphocytes to produce a pro-inflammatory T-helper 17 (TH17) phenotype. Therefore, we hypothesized sympathetic-driven neuroimmune interactions could mediate psychological trauma-induced T-lymphocyte inflammation. MethodsRepeated social defeat stress (RSDS) is a preclinical murine model that recapitulates the behavioral, autonomic, and inflammatory aspects of PTSD. Targeted splenic denervation (Dnx) was performed to deduce the contribution of splenic sympathetic nerves to RSDS-induced inflammation. Eighty-five C57BL/6J mice underwent Dnx or sham-operation, followed by RSDS or control paradigms. Animals were assessed for behavioral, autonomic, inflammatory, and redox profiles. ResultsDnx did not alter the antisocial or anxiety-like behavior induced by RSDS. In circulation, RSDS Dnx animals exhibited diminished levels of T-lymphocyte-specific cytokines (IL-2, IL-17A, and IL-22) compared to intact animals, whereas other non-specific inflammatory cytokines (e.g., IL-6, TNF-, and IL-10) were unaffected by Dnx. Importantly, Dnx specifically ameliorated the increases in RSDS-induced T-lymphocyte mitochondrial superoxide, TH17 polarization, and pro-inflammatory gene expression with minimal impact to non-T-lymphocyte immune populations. ConclusionsOverall, our data suggest that sympathetic nerves regulate RSDS-induced splenic T-lymphocyte inflammation, but play a minimal role in the behavioral and non-T-lymphocyte inflammatory phenotypes induced by this psychological trauma paradigm.

animal behavior and cognition↗

bioRxiv2020

Inflammation is a stronger predictor of psychological trauma exposure than behavior in repeated social defeat

Post-traumatic stress disorder (PTSD) is a psychiatric illness that results in an increased risk for a variety of inflammatory diseases. The exact etiology of this increased risk in unknown, and thus, several animal models have been developed to investigate the neuroimmune interactions of PTSD. Repeated social defeat stress (RSDS) is an established preclinical model of psychological trauma that recapitulates certain behavioral and inflammatory aspects of human PTSD. Furthermore, RSDS has been utilized to subgroup animals into susceptible and resilient populations based on one specific behavioral phenotype (i.e., social interaction). Herein, we conducted an extensive investigation of circulating inflammatory proteins after RSDS, and found significant elevations in various cytokines and chemokines after exposure to psychological trauma. When categorizing animals into either susceptible or resilient populations based on social interaction, we found no inflammatory or other behavioral differences between these subgroups. Furthermore, assessment of associations between all detectable inflammatory proteins and behavioral outputs found no significant correlation between social interaction parameters and inflammation. In contrast, we identified a panel of 5 circulating inflammatory proteins that showed significant associations with elevated zero maze parameters. Strikingly, these 5 circulating inflammatory proteins displayed a stronger predictive ability of psychological trauma exposure compared to any behavioral outcome. These findings provide new insights into inflammatory markers associated with RSDS, and their ability to predict psychological trauma exposure more robustly than commonly utilized behavioral paradigms. HighlightsO_LIRepeated social defeat stress (RSDS) reproducibly produces peripheral inflammation C_LIO_LIPeripheral inflammation is not coupled to social interaction testing parameters C_LIO_LISusceptible and resilient categorization does not reflect peripheral inflammation C_LIO_LIAnxiety-like behavioral parameters are linked to peripheral inflammation in RSDS C_LIO_LIPeripheral inflammation is more predictive of trauma than behavior in RSDS C_LI

animal behavior and cognition↗