The CCR4 receptor is expressed by Th17 and regulatory T cells, and an imbalance between these two T cell subpopulations is thought to drive autoimmunity and its associated chronic inflammation. CCL17 and CCL22 are the functional ligands of the CCR4 receptor. These chemokines share a nucleotide homology of 32% and are found in close proximity to each other on both the human and mouse chromosomes. Despite their similarity, they are variably expressed in rheumatoid arthritis (RA), where CCL17 is highly upregulated in the synovial fluid of patients and CCL22 is detected at very low levels. This expression suggests that these chemokines are regulated differently.
GM-CSF and its receptor are currently being targeted in clinical trials for RA. GM-CSF is highly upregulated in the synovial fluid of RA patients, and it has also been shown to upregulate CCL17 expression. IL4 is another cytokine that upregulates CCL17 expression, but it is detected at very low levels in RA patients. These cytokines have contrasting roles in inflammation but they both upregulate CCL17 production by promoting JMJD3 demethylase activity and IRF4 expression.
We report here that GM-CSF and IL4 upregulates CCL22 expression in human monocytes, human macrophages, and mouse macrophages. Its upregulation is variably dependent on JMJD3 and IRF4 in these cell types, which suggests distinct signalling pathways in different cell types. Moreover, GM-CSF and IL4 independently activate the transcription factors STAT5 and STAT6, respectively, and their activation is crucial for CCL17 and CCL22 expression in all three cell types. This variable regulation of these seemingly similar chemokines sheds light on the nuances of cell types and their role in autoimmune diseases. As therapies begin targeting more specific, downstream mediators, delineating the signalling pathways activated by key inflammatory cytokines, and discerning differences between immune cell types, will increase the efficacy of future therapies.