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Disruption of Mitochondrial Redox and Metabolic States in Norepinephrine‐Exposed T‐lymphocytes
Author(s) -
Case Adam J.,
Collins Christopher W.,
Roessner Colton T.,
Tian Jun,
Zimmerman Matthew C.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.697.8
Subject(s) - mitochondrion , mitochondrial ros , bioenergetics , immune system , oxidative stress , microbiology and biotechnology , chemistry , cd8 , cytokine , respiratory burst , biology , endocrinology , medicine , immunology
Increased sympathoexcitation and norepinephrine (NE) outflow are hallmarks of chronic diseases such as heart failure, hypertension, diabetes, and even psychological stress. NE has been demonstrated to modulate the immune system, but mechanisms controlling this cross‐talk between the autonomic nervous and immune systems are complex and poorly defined. Recently, using a mouse model of elevated NE we elucidated that NE utilizes superoxide (O 2 •− )‐dependent redox signaling to modulate T‐lymphocyte function. However, the source of this O 2 •− and how it mechanistically contributes to T‐lymphocyte function remain elusive. Due to growing evidence that metabolism is a key regulator of T‐lymphocyte activation and differentiation, we hypothesized that NE mediates its effects on T‐lymphocytes via disruption of mitochondrial bioenergetics and redox state. To address this hypothesis, we utilized purified mouse splenic CD4+ and CD8+ T‐lymphocytes stimulated with NE and assessed subcellular O 2 •− levels, mitochondrial metabolism, cellular proliferation/differentiation, and cytokine profiles. First, we demonstrated the source of O 2 •− was indeed the mitochondria as evidenced by a 50% increase (p<0.01 vs vehicle) in MitoSOX Red oxidation as well as the attenuation of this signal by the addition of the mitochondrial‐targeted O 2 •− scavenging antioxidant MitoTempol. NE‐stimulated T‐lymphocytes also demonstrated a 25% (p<0.05 vs vehicle) decrease in mitochondrial respiratory capacity, which suggests disruption of mitochondrial metabolism and the potential source of increased mitochondrial O 2 •− . Next, NE inhibited proliferation of T‐lymphocytes by approximately 50% (p<0.01 vs vehicle), which was accompanied by a concomitant increase in the percentage of cells remaining in their naïve state (49.5% with NE vs 26.4% with vehicle, p<0.01). Interestingly, NE lead to significant increases (ranging from 1.8–4.1 fold, p<0.05) in O 2 •− levels in all T‐lymphocytes independent of activation state ( i.e . naïve, memory, and effector). Last, mitochondrial O 2 •− was shown to be mechanistic to the NE‐mediated T‐lymphocyte phenotype as supplementation of MitoTempol could significantly reverse the approximate 50% decreases in IL‐2 and interferon gamma (p<0.01) and 2‐fold increases in IL‐6 and IL‐17 (p<0.01) levels observed with NE treatment. However, the decreases in proliferation could not be reversed by increased mitochondrial O 2 •− scavenging. Overall, our data suggest the potential for a new paradigm involving mitochondrial redox and metabolism as mechanistic elements in the regulation of T‐lymphocyte function by NE. Support or Funding Information This work is supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) R00HL123471 (to AJC) and R01HL103942 (to MCZ).