Abstract
The innate immune response plays a key role in fighting infection by activating inflammation and stimulating the adaptive immune response. However, chronic activation of innate immunity can contribute to the pathogenesis of many diseases with an inflammatory component. Thus, various negatively acting factors turn off innate immunity subsequent to its activation to ensure that inflammation is self-limiting and to prevent inflammatory disease. These negatively acting pathways include the production of inhibitory acting alternate proteins encoded by alternative mRNA splice forms of genes in Toll-like receptor (TLR) signaling pathways. We previously found that the SF3a mRNA splicing complex was required for a robust innate immune response; SF3a acts to promote inflammation in part by inhibiting the production of a negatively acting splice form of the TLR signaling adaptor MyD88. Here we inhibit SF3a1 using RNAi and subsequently perform an RNAseq study to identify the full complement of genes and splicing events regulated by SF3a in murine macrophages. Surprisingly, in macrophages, SF3a has significant preference for mRNA splicing events within innate immune signaling pathways compared with other biological pathways, thereby affecting the splicing of specific genes in the TLR signaling pathway to modulate the innate immune response.
Highlights
While the innate immune response plays a critical role in fighting infection, overactive or chronically activated innate immunity can contribute to many diseases with an inflammatory component [1,2,3,4]
We previously found that the SF3a mRNA splicing complex was required for a robust innate immune response; SF3a acts to promote inflammation in part by inhibiting the production of a negatively acting splice form of the Toll-like receptor (TLR) signaling adaptor MyD88
Within minutes after we are exposed to pathogens, our bodies react with a rapid response known as the “innate immune response.”
Summary
While the innate immune response plays a critical role in fighting infection, overactive or chronically activated innate immunity can contribute to many diseases with an inflammatory component [1,2,3,4]. To fight infection without inducing inflammatory disease, a complex regulatory system has evolved to activate innate immunity when humans are exposed to pathogens and turn the system off after a period of time to ensure that it is self-limiting. Binding of LPS to TLR4 and its co-receptor MD-2 leads to recruitment and activation of the signaling adaptor MyD88, which in turn recruits a family of related kinases: IRAK4, IRAK1, and IRAK2 [7]. This signaling cascade continues, culminating in the activation of the transcription factor NFkB and the activation of several MAP kinase pathways [7]. This in turn leads to the production of, among other things, inflammatory cytokines
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