Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice

Abstract

Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1β and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.

Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2−/− mice

“…Core body temperature was also significantly different after 6 hours of LPS injections at the time that symptoms of sickness were maximal. While LPS can induce both hyper or hypothermia depending on the species, strain and dosage of LPS, hypothermic responses to LPS challenge are very common [38, 39] and usually parallel symptoms of sickness behavior. These effects in Rag2 −/− mice were accompanied by an attenuated peripheral TNF-α response in the hypothalamus when compared to BALB/c mice.…”

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

“…In agreement with the transactivation mechanism, GR dim mice show a reduced ability to activate transcription in the liver in response to exogenous ligands (Frijters et al 2010). However, later studies were inconsistent with expectations for transrepression by revealing that GR dim mice exhibit a diminished response to GC treatment in inflammatory paradigms such as TNF-induced inflammation (Vandevyver et al 2012), LPSand CLP-induced sepsis (Kleiman et al 2012;Silverman et al 2013), antigen-induced rheumatoid arthritis (Baschant et al 2011(Baschant et al , 2012, allergic contact dermatitis (Kleiman and Tuckermann 2007), and experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis (Schweingruber et al 2014). This was in part due to the inability of GR dim to induce GR-dependent antiinflammatory genes (Vandevyver et al 2012).…”

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

“…These mice express a point mutant version of GR, where Alanine 465 is changed to a Threonine (A465T and in human GR A458T), located in the second zinc finger motif of the DBD, leading to reduced homodimerisation of the GR and subsequent reduced binding to GRE elements (Heck et al, 1994;Reichardt et al, 1998;Lim et al, 2015). Interfering with the dimerisation interface strongly abrogates the antiinflammatory actions of endogenous GCs, as GR dim mice are highly susceptible for several inflammatory disease models (Nixon et al, 2013;Vandevyver et al, 2013), such as TNF-and LPS-induced acute inflammation Tuckermann et al, 2007;Hübner and Tuckermann, 2012;Kleiman et al, 2012;Vandevyver et al, 2012a,b;Silverman et al, 2013) and CLP (cecal ligation and puncture)-induced sepsis Kleiman et al, 2012) (Table 1). In addition, GR dimerisationdependent actions are also indispensable in the protection by exogenous GCs during rheumatoid arthritis (Baschant et al, 2011;Baschant et al, 2012) and allergic contact dermatitis Tuckermann et al, 2007) (Table 1).…”