Monocytes or tissue-resident macrophages are key components of the innate immune system and are the first line of defence against invading pathogens or tissue injury. The expression of inflammatory genes is rapidly upregulated upon detection of an infection, or during cell damage. These genes mediate a potent inflammatory response which must then be downregulated, once the infection or damage has been resolved. Without proper control, the continued expression of inflammatory genes and chronic activation of the immune response contributes to diseases such as psoriasis, arthritis, and diabetes.
The genes that modulate inflammatory responses are tightly regulated by transcription factors (TFs), which form complex feedback loops to activate and repress gene expression. While many of these factors are known, the interactions between specific TFs to induce or repress inflammatory genes are incompletely understood.
Mice with a genetic deletion in the TF Klf3 have an inflammatory phenotype, with increased macrophages. RNA-sequencing of bone-marrow derived macrophages from KLF3-null mice revealed an enhanced response to bacterial endotoxin (LPS). In cell line models, over-expression of KLF3 results in a perturbed response to LPS stimulation. Using chromatin immunoprecipitation sequencing (ChIPseq) we have identified a novel interaction between KLF3 and the pioneering TF PU.1 at key inflammatory genes.
We now further explore this interaction and investigate the role of KLF3 in the complex transcriptional networks that govern inflammatory gene expression and how dysregulation of these contributes to inflammatory disease.