The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges

Abstract

Inflammation is a fundamental response of the immune system whose successful termination involves the elimination of the invading pathogens, the resolution of inflammation and the repair of the local damaged tissue. In this context, the interleukin 10 (IL-10)-mediated anti-inflammatory response (AIR) represents an essential homeostatic mechanism that controls the degree and duration of inflammation. Here, we review recent work on the mechanistic characterization of the IL-10-mediated AIR on multiple levels: from the cataloguing of the in vivo genomic targets of STAT3 (the transcription factor downstream of IL-10) to the identification of specific co-factors that endow STAT3 with genomic-binding specificity, and how genomic and computational methods are being used to elucidate the regulatory mechanisms of this essential physiological response in macrophages.

Keywords: IL-10; JAK1; STAT3; anti-inflammatory response; bioinformatics; macrophages; transcriptional regulatory modules.

Figure 1:

The IL-10 AIR in the context of inflammation. The TLR-initiated inflammatory response activates a set of well-understood signalling pathways, which ultimately lead to the expression of thousands of pro-inflammatory genes. IL-10 initiates the AIR upon binding to its cognate receptor, where JAK1 phosphorylates STAT3. Neither IL-10, the IL-10R, the Janus kinase or STAT3 can be functionally replaced in this pathway. Upon entering the nucleus, STAT3 activates specific target genes among which the ultimate effectors of the AIR (the ‘AIR factors’) are found. The AIR factors repress the expression of pro-inflammatory genes mostly at the transcriptional level, with only ∼20% of the genes activated by LPS in macrophages eventually being repressed by IL-10. Adapted from Murray [11].

Figure 2:

Characterization of TRMs. (A) The goal of the rTRM method is to reconstruct TRMs by integrating multiple data sources. Starting with a set of experimentally characterized genomic-binding sites (e.g. from ChIP-seq) (1), these sites are investigated for the presence of over-represented TF binding motifs using computational approaches (2). The over-represented motifs are matched to their corresponding TFs, and these are further filtered by expression data from the same cell type (3). Finally, rTRM harnesses the power of PPIs by investigating the entire PPI space from the BioGRID database to build TRMs from the TFs that have survived the previous filtering steps. (B) The genomic-binding patterns of STAT3 encode two distinct modes of regulation: a ‘macrophage-specific’ regulatory mode characterized by a specific set of co-TFs and co-factors (left panel) and a ‘universal’ regulatory mode characterized by a distinct TRM. Whereas the universal mode of STAT3 regulation serves to perpetuate STAT3 signalling and fine-tune the JAK-STAT pathway, the macrophage-specific mode is responsible for the AIR.

Figure 3:

The IL-10/JAK1/STAT3 anti-inflammatory pathway: current state of affairs. The ChIP-seq of STAT3 in IL-10-stimulated macrophages, coupled with RNA-seq, has unveiled the repertoire of genes that are activated by STAT3 during the AIR. Among these the AIR factors shall be found, followed by a detailed characterization of the AIR factor-target gene relationships, and their mechanisms. Another fundamental aspect of the AIR that needs addressing is the role that the epigenetic landscape plays in regulating the AIR, as well as the potential regulation of the AIR by STAT3-induced enzymes, such as PTP1B, a tyrosine phosphatase previously shown to target phospho-STAT3 [56]. An integrated understanding of the AIR factors and their mechanisms of action on their targets, the genomic regulation of the AIR by specific TRMs and by the epigenetic landscape, as well as the cytoplasmic-level regulation of the AIR will provide us with an unprecedented degree of detail on this essential physiological response that we may harness to develop tailored anti-inflammatory therapies.