Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

Abstract

Mutual regulation and balance between the endocrine and immune systems facilitate an organism's stress response and are impaired following chronic stress or prolonged immune activation. Concurrent alterations in stress physiology and immunity are increasingly recognized as contributing factors to several stress-linked neuropsychiatric disorders including depression, anxiety, and post-traumatic stress disorder. Accumulating evidence suggests that impaired balance and crosstalk between the glucocorticoid receptor (GR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) - effectors of the stress and immune axes, respectively - may play a key role in mediating the harmful effects of chronic stress on mood and behavior. Here, we first review the molecular mechanisms of GR and NFκB interactions in health, then describe potential shifts in the GR-NFκB dynamics in chronic stress conditions within the context of brain circuitry relevant to neuropsychiatric diseases. Furthermore, we discuss developmental influences and sex differences in the regulation of these two transcription factors.

Keywords: Anxiety; Depression; FKBP5; Glucocorticoid receptor; Glucocorticoid resistance; Inflammation; Nuclear factor kappa-light-chain-enhancer of activated B cells; PTSD; Stress.

Figure 1

A. Molecular Regulation of GR Activity of the GR is regulated at multiple levels. Glucocorticoids (CORT), the ligand for the GR, promote nuclear translocation activity of the GR (a.). Co-chaperones of the GR such as FKBP5 (b.) and FKBP4 (c.) impair or promote GR nuclear translocation respectively. The GR is phosphorylated (d.) at multiple sites which may increase or decrease GR activity, and furthermore, the phosphorylation status of GR may alter the transcriptional profile, providing fine-tuning of the genes GR up or down-regulates. Ubiquitination (e.) promotes degradation of the GR, reducing GR activity. Expression of GRβ (f.) may decrease activity of the GR, and increased efflux of the ligand CORT from the cell due to increased p-glycoprotein activity (g.) may also decrease activity of GR. Altered transcription of Nr3c1 (h.) may also impact GR expression and activity. B. Molecular Regulation of NFκB. The canonical and non-canonical NFκB pathways reside in the cytoplasm, tethered by the inhibitor protein IκBα/p100/p105. Following TAK1-mediated activation by TNF, IL-1, and Toll-like receptor transduction pathways, the canonical IKK complex phosphorylates IκBα, thus releasing the p65-p50 heterodimer to translocate to the nucleus. In the non-canonical pathway, following activation by lymphotoxin-β receptor or CD40 ligand signaling, IKKα phosphorylates p100/p105, thus triggering their cleavage into p52/p50. The newly freed p52/p50-RelB complex then translocates into the nucleus. The NFκB complex may be subject to further post-translational modifications including phosphorylation and acetylation prior to binding to the κREs.

Figure 1

A. Molecular Regulation of GR Activity of the GR is regulated at multiple levels. Glucocorticoids (CORT), the ligand for the GR, promote nuclear translocation activity of the GR (a.). Co-chaperones of the GR such as FKBP5 (b.) and FKBP4 (c.) impair or promote GR nuclear translocation respectively. The GR is phosphorylated (d.) at multiple sites which may increase or decrease GR activity, and furthermore, the phosphorylation status of GR may alter the transcriptional profile, providing fine-tuning of the genes GR up or down-regulates. Ubiquitination (e.) promotes degradation of the GR, reducing GR activity. Expression of GRβ (f.) may decrease activity of the GR, and increased efflux of the ligand CORT from the cell due to increased p-glycoprotein activity (g.) may also decrease activity of GR. Altered transcription of Nr3c1 (h.) may also impact GR expression and activity. B. Molecular Regulation of NFκB. The canonical and non-canonical NFκB pathways reside in the cytoplasm, tethered by the inhibitor protein IκBα/p100/p105. Following TAK1-mediated activation by TNF, IL-1, and Toll-like receptor transduction pathways, the canonical IKK complex phosphorylates IκBα, thus releasing the p65-p50 heterodimer to translocate to the nucleus. In the non-canonical pathway, following activation by lymphotoxin-β receptor or CD40 ligand signaling, IKKα phosphorylates p100/p105, thus triggering their cleavage into p52/p50. The newly freed p52/p50-RelB complex then translocates into the nucleus. The NFκB complex may be subject to further post-translational modifications including phosphorylation and acetylation prior to binding to the κREs.

Figure 2. Cytoplasmic interactions between GR and NFκB cascades

The co-chaperone FKBP5 has been identified as a binding partner to multiple proteins constituting the NFκB pathway including TAK1, IKKα, and p65. Furthermore, the chaperone proteins CDC37, Hsp90, and Hsc70 also bind IKKα and p65. The functional significance of these protein-protein interactions remain incompletely understood.

Figure 3. Nuclear interactions between GR and NFκB cascades

The GR interacts with GREs (a.) and negative GREs (b.) to promote or suppress gene expression at numerous target genes. Interactions with these regulatory elements can be reduced by interactions between GR and NFκB. Interaction of GR with the p65 subunit of NFκB (c.) can also inhibit NFκB transcriptional activity at κBREs. Finally, some reports suggest that GR can promote nuclear export of NFκB, further reducing its transcriptional activity.

Figure 4. GR and NFκB in glucocorticoid resistance in the brain and immune system

Under acute stress conditions, release of catecholamines by the sympathetic nervous system activates NFκB within peripheral immune cells, and leads to expression of cytokines and chemokines. Activation of the hypothalamic-pituitary adrenal axis results in the release of glucocorticoids, and GR suppresses NFκB in peripheral immune cells. Under chronic stress conditions, impaired GR activity within peripheral myeloid cells can disinhibit NFκB-mediated inflammation. In turn, glucocorticoid-resistant, hyper-inflammatory immune cells can traffic into the brain, eventually getting recruited to brain regions regulating the stress response. The GR-mediated negative feedback regulation of HPA axis is also impaired in chronic stress pathology, thus further perpetuating stress-induced neuroinflammation. The disruption in endocrine-immune balance appears to be due partly to primed microglia that display decreased GR sensitivity, pro-inflammatory GR, and exaggerated innate immune activation including increased NFκB and Toll-like Receptor signaling. The functional significance of the altered GR-NFκB balance may be manifested in the brain as altered synaptic plasticity and neurotransmission.