Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

Abstract

Although females suffer twice as much as males from stress-related disorders, sex-specific participating and pathogenic cellular stress mechanisms remain uncharacterized. Using corticotropin-releasing factor receptor 2-deficient (Crhr2−/−) and wild-type (WT) mice, we show that CRF receptor type 2 (CRF2) and its high-affinity ligand, urocortin 1 (Ucn1), are key mediators of the endoplasmic reticulum (ER) stress response in a murine model of acute pancreatic inflammation. Ucn1 was expressed de novo in acinar cells of male, but not female WT mice during acute inflammation. Upon insult, acinar Ucn1 induction was markedly attenuated in male but not female Crhr2r−/− mice. Crhr2−/− mice of both sexes show exacerbated acinar cell inflammation and necrosis. Electron microscopy showed mild ER damage in WT male mice and markedly distorted ER structure in Crhr2−/− male mice during pancreatitis. WT and Crhr2−/− female mice showed similarly distorted ER ultrastructure that was less severe than distortion seen in Crhr2−/− male mice. Damage in ER structure was accompanied by increased ubiquitination, peIF2, and mis-targeted localization of vimentin in WT mice that was further exacerbated in Crhr2−/− mice of both sexes during pancreatitis. Exogenous Ucn1 rescued many aspects of histological damage and cellular stress response, including restoration of ER structure in male WT and Crhr2−/− mice, but not in females. Instead, females often showed increased damage. Thus, specific cellular pathways involved in coping and resolution seem to be distinct to each sex. Our results demonstrate the importance of identifying sex-specific pathogenic mechanisms and their value in designing effective therapeutics.

Ultrastructure and immunohistochemical characterization of proteins concerned with the secretory machinery in goat ceruminous glands

“…On the other hand, the concentric ER-derived structures, similar to SARC-like body, are detected in the acinar cells of pancreatitis induced by overstimulation of cerulein, a cholecystokinin analogue, in male mouse. 33 These findings support the view that the goat ceruminous glandular cells have highly secretory activity. Furthermore, the activation of IRE1α may participate in the homeostatic maintenance of these cells.…”

Urocortin 3 expression at baseline and during inflammation in the colon: Corticotropin releasing factor receptors cross-talk

“…Others and we have reported that Ucn1 actions are anti-inflammatory in the periphery [13,20], but the role of Ucn3 in mediating inflammation in the gut remains unknown. Rats with TNBS colitis failed to gain weight throughout the course of our study (Fig.…”

“…It is known that infusion of Ucn1 can ameliorate both colonic and pancreatic inflammation [13,20]. Whether Ucn3 is involved in the pathogenesis of GI disorders, such as Crohn’s colitis has not been studied before.…”

“…Moreover, Ucn3 mRNA showed a correlation with histology score ( r 2 = 0.495), suggesting that changes in Ucn3 seen during colitis are secondary to changes in expression of other urocortins (Ucn1–2) or CRF 2 , creating a feedback loop. Thus, unlike Ucn1 that reduces inflammation during colitis [13] or acute pancreatitis in a gender-specific manner [20], Ucn3 does not appear to have an overt role in the initiation or prevention of inflammation.…”

Endocrinology and the brain: corticotropin-releasing hormone signaling

“…The mechanism of desensitization has received special attention considering that the failure of this signal regulation during recurrent exposure to stress may be causally related to pathological conditions ( 20 ) or the sex differences observed in the receptor rate of internalization could explain the increased vulnerability of females to stress-related disorders ( 136 ). Sex-dependent mechanisms have also been described in CRHR2 and UCN1-mediated stress-mediated inflammation responses ( 137 , 138 ).…”