The Conserved Transcriptional Response to Adversity

Abstract

Gene expression profiling studies of people exposed to chronic threat have identified a Conserved Transcriptional Response to Adversity (CTRA) in circulating immune cells. This physiological pattern is characterized by up-regulated expression of genes involved in inflammation and down-regulated expression of genes involved in Type I interferon responses. The CTRA is mediated by beta-adrenergic signaling pathways that transduce sympathetic nervous system activity into changes in transcription factor activity and hematopoietic output of myeloid lineage immune cells (monocytes, neutrophils, and dendritic cells). Recent research has begun to identify the CNS processes that regulate peripheral CTRA activity, define its implications for disease, and explore the role of positive psychosocial factors in buffering such effects. The CTRA provides a genomic framework for understanding PNI relationships and connecting macro-level psychosocial processes to the micro-level biology of health and disease.

Conflict of interest statement

Conflict of interest The author declares no conflict of interest.

Figures

Figure 1 –. CTRA signal transduction.

The “social signal transduction” pathway that drives CTRA gene expression involves extended exposure to adverse environmental conditions, which results in activation of evolutionarily conserved threat response systems in the central nervous system (CNS), resulting in activation of fight-or-flight stress responses from the sympathetic nervous system (SNS) and release of the nerurotransmitter, norepinephrine, from sympathetic nerve terminals. These signals are transduced by leukocyte beta-adrenergic receptors into activation of intracellular second messenger systems such as the cyclic-3’−5’-adenosinemonophosphate / protein kinase A (cAMP/PKA) pathway, which exert diverse effects on multiple transcription control pathways such as increased activity of the cAMP response element binding factor (CREB) family, increased activity of the pro-inflammatory NF-κB/Rel and activator protein 1 (AP-1) transcription factor families, and decreased activity of interferon response factors (IRF). Differential activation of these transcription factor families results in up-regulated transcription of pro-inflammatory genes and down-regulated transcription of Type I interferon antiviral genes, resulting in downstream alterations in inflammatory and antiviral immune responses (including cytotoxic T lymphocytes; CTL) and consequent alterations in the risk of inflammation-related diseases such as coronary heart disease (CHD), Alzheimer’s Disease (AD), tumor development and metastasis, and viral infection. In addition to direct regulation of gene transcription in existing cells, SNS nerve fiber activation in the bone marrow also results in increased production of myeloid lineage immune cells (particularly classical monocytes), resulting in a pro-inflammatory bias in the circulating leukocyte pool.

Figure 2 –. Multi-level assessment of the CTRA.

The CTRA immunoregulatory pattern can be assessed at multiple levels of the “social signal transduction” cascade outlined in Figure 1, including up-regulated activity of pro-inflammatory transcription factors and down-regulated activity of antiviral transcription factors (e.g., through bioinformatic analyses of gene regulation, electrophoretic mobility-shift assays/EMSA, or chromatin immunoprecipitation/ChIP assays); up-regulated expression of pro-inflammatory effector genes (e.g., IL1B, IL6, IL8, TNF) and down-regulated expression of interferon response genes (e.g., IFI-, MX-, and OAS-family genes) as assessed by RNA sequencing (RNAseq) and Gene Ontology (GO) analyses; up-regulated production of classical monocytes and down-regulated prevalence of non-classical monocytes (e.g., as assessed by flow cytometry, bioinformatic analysis of leukocyte transcriptome profiles by Transcript Origin Analysis/TOA or Transcriptome Representation Analysis/TRA, or cell type-specific DNA methylation signatures); up-regulated functional bioassays of inflammation and/or down-regulated antiviral or cytotoxic T lymphocyte (CTL) responses; or epidemiologic increases in CTRA-related diseases such as coronary heart disease (CHD), Alzheimer’s Disease (AD), metastatic cancer, and viral infections.