A novel role for XIST in modulating gender specific inflammatory response
Botros Shenoda1, Guillermo Alexander2, Enrique Aradillas Lopez2 and Seena Ajit1
1
Pharmacology & Physiology, 2Neurology, Drexel University College of Medicine, Philadelphia, PA
19102
Introduction: Inflammatory and immune responses differ between the sexes. The levels of inflammatory
cytokines also vary between males and females. X-chromosome inactivation is a complex epigenetic
phenomenon and XIST (X-inactive specific transcript), a long non-coding RNA is crucial for mediating
X-chromosome inactivation in female cells. Here we propose that female specific XIST expression may
play a role in mediating sexual dimorphism in inflammatory response.
Methods: To understand the role of XIST in mediating inflammatory response, we altered the expression
of Xist under inflammatory stimuli using molecular and pharmacological tools. We investigated XIST
expression in whole blood as well as sorted immune cells from patients with complex regional pain
syndrome (CRPS) a chronic inflammatory and neuropathic pain condition.
Results: Our results have shown that the expression of Xist in murine female macrophages is upregulated
under inflammatory states through NF-κB mediated pathway, concomitantly decreasing proinflamamtory
cytokines. XIST was also regulated by anti-inflammatory glucocorticoids, beta estradiol, and miR-34a
and miR-181a, two microRNAs involved in mediating inflammatory response. Immune cells isolated
from CRPS patients show reduced XIST levels relative to control while circulating XIST was
significantly elevated in female CRPS patients relative to healthy controls. High circulating levels of
XIST were also observed in female CRPS patients resistant to intravenous ketamine treatment.
Conclusion: Collectively, these data indicate that miRNA mediated regulation of XIST in female cells
may regulate inflammation associated with CRPS, and this miRNA-XIST-inflammation axis is modulated
by beta estradiol. Our results reveal a novel function for XIST beyond X-chromosome inactivation. By
suppressing excessive inflammatory response, XIST may contribute to lower levels of inflammatory
cytokines in female patients relative to males.
Fund: Botros Shenoda is a recipient Fulbright grant funded by the US department of the state and Dean’s
Fellowship for Excellence in Collaborative or Themed Research from Drexel College of Medicine. This
study was supported by funds from NINDS 1R21NS082991, Rita Allen Foundation and Drexel University
Clinical and Translational Research Institute award to Seena Ajit.