Splicing Regulation of Pro-Inflammatory Cytokines and Chemokines: At the Interface of the Neuroendocrine and Immune Systems

Abstract

Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90% of human genes undergo alternative splicing, and alternative splicing is especially prevalent in the nervous and immune systems, tissues where cells need to react swiftly and adapt to changes in the environment through carefully regulated mechanisms of cell differentiation, migration, targeting, and activation. Given its prevalence and complexity, this highly regulated mode of gene expression is prone to be affected by disease. In the following review, we look at how alternative splicing of signaling molecules—cytokines and their receptors—changes in different pathological conditions, from chronic inflammation to neurologic disorders, providing means of functional interaction between the immune and neuroendocrine systems. Switches in alternative splicing patterns can be very dynamic and can produce signaling molecules with distinct or antagonistic functions and localization to different subcellular compartments. This newly discovered link expands our understanding of the biology of immune and neuroendocrine cells, and has the potential to open new windows of opportunity for treatment of neurodegenerative disorders.

METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide‐induced inflammatory response in human dental pulp cells

“…More than 90% of human genes undergo alternative splicing, which is especially prevalent in the immune system 57. Alternative splicing can regulate intracellular signalling and intercellular communication through the expression of diverse isoforms of cytokines, cytokine receptors, kinases, phosphatases and adaptor proteins 58.…”

Altered Neuroendocrine Immune Responses, a Two-Sword Weapon against Traumatic Inflammation

“…The cross-regulation of neuroendocrine and immune system further endows them with the ability to stringently respond to various endogenous and endogenous stressful signals in trauma. The tightly regulated network comprising endoplasmic reticulum stress 81 , 129 , apoptosis and autophagy 130 , 131 , microenvironment regulation, post-transcriptional splicing 132 , post-translational modifications and metabolic regulations 133 , 134 is essential for the appropriate orchestration of traumatic inflammation and for the prevention of harmful traumatic complications (acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome, (MODS)).…”

Inflammation Drives Alternative First Exon usage to Regulate Immune Genes including a Novel Iron Regulated Isoform of Aim2

“…Alternative splicing within the immune system can affect the type and magnitude of the inflammatory response, such as the production of a soluble form of TLR4 that is expressed upon LPS, which leads to inhibition of TNFα and NFκB serving as a negative feedback mechanism (19,20). Additionally, this mechanism has been characterized within signaling molecules (21,22), including TBK1 (23) and MyD88 (24), that produce the alternative RNA splice forms, TBK1s and MyD88s respectively, which function to limit the extent of the proinflammatory response. Alternative splicing can also result in the production of inflammatory signaling molecules, such as TRIF (25) and the proteins in the NFκB family (9) with altered activity or stability.…”