An altered peripheral IL6 response in major depressive disorder

Abstract

Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of antidepressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated proinflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1β, TNFα, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients.

Explore the Underlying Mechanism Between Atopic Dermatitis and Major Depressive Disorder

“…Moreover, five genes were enriched in three immune system-related pathways [p-value: (0.00011, 0.00096); GO ID: 0002822; 0002819; and 0002700]. These pathways were previously implicated in the development of MDD (Kim et al, 2012;Miller and Raison, 2016;Money et al, 2016). For detailed information on these significantly enriched pathways, please refer to Supplementary Material AD_MDD→PEA.…”

Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study

“…The crosstalk between inflammatory abnormalities and affective disorders has been extensively investigated from various perspectives, including cytokines, chemokines, antibody titers and immune cell numbers34567. Albeit remarkably diverse, consistent findings exist on the blood level change of several cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), during the acute or chronic phase of major depression (MD) and bipolar II disorder depression (BD)89.…”

Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

“…Pro-inflammatory cytokines such as interleukin-6 and -1 beta (IL-6 and IL1-β) and tumor necrosis factor-alpha (TNF-α) are expressed by HDF and these cells are sensitive to extracellular inflammatory signals [ 56 ]. One study investigated HDF after in vitro treatment with the pro-inflammatory cytokine IL-6, reporting a blunted response (calculated on the expression of a set of genes usually increased by IL-6 treatment) in HDF from MDE patients as compared to healthy controls [ 24 ]. The same group identified a diminished pentraxin-3 mRNA expression in HDF from MDE patients as compared to healthy controls HDF.…”

“…Noteworthy, depression and obesity are associated and share biological pathway dysregulations such as leptin increased expression, reduced insulin sensitivity and chronic inflammation [ 123 , 154 ]. Interestingly, HDF expressed the leptin receptor and are sensitive to inflammatory cytokines [ 24 ]. Moreover, HDF express nucleotide-binding oligomerization domain (NOD)-like receptor 3 (NLRP3), a protein involved in inflammasome regulation [ 124 ].…”

“…When compared to the other main in vitro human models which are leukocytes, immortalized human lymphocytes (lymphoblastoid cells), olfactory epithelium, induced pluripotent stem cells and induced neural cells, HDF are a good compromise to study brain-related diseases [ 9 ]. Several investigations of HDF from patients with mental disorders (bipolar disorder, major depression disorder and schizophrenia) have evidenced biological impairments such as oxidative homeostasis dysfunctions [ 21 - 23 ], inflammation [ 24 ] and modified metabolic activities [ 25 ]. In the context of mental disorders studies, HDF have been used as a sensor of these peripheral biological impairments [ 9 ], as well as a reflection of brain cell biological mechanisms (circadian rhythms, response to psychotropic drugs, pathways such as serotoninergic and adrenergic signaling) [ 26 - 29 ].…”