IL-10R and Non-Canonical Mitochondrial STAT3 Signaling in the Regulation Macrophage Function and Inflammation

Abstract

Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine that plays a critical role in immune responses and the control of inflammation in diseases such as inflammatory bowel disease. IL-10 signals through signal transducer and activator of transcription 3 (STAT3), a master transcription factor that works by inducing gene transcription in the nucleus. Here we demonstrate in macrophages that in addition to nuclear STAT3, IL-10 induces phosphorylated STAT3 in the mitochondria. Impairment of STAT3 mediated transcription produced distinct outcomes in M1 and M2 macrophages upon IL-10 stimulation. The suppression of LPS-induced genes, inflammatory surface markers, and dysfunctional mitochondria was still seen in conditions with impaired STAT3 transcription. However, STAT3 mediated transcription was required for IL-10 mediated M2r macrophage polarization. Our findings suggest that mitochondrial STAT3 may play a key role in specifically restraining inflammatory gene expression after inflammatory stimuli.