Biology subjects

Pitts, L. J.

Publications and source records attributed to Pitts, L. J..

3 recordsLinked to original sources

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↗