Unphosphorylated STAT3 modulates alpha7 nicotinic receptor signaling and cytokine production in sepsis

Abstract

The role of STAT3 in infectious diseases remains undetermined, in part because unphosphorylated STAT3 has been considered an inactive protein. Here, we report that unphosphorylated STAT3 contributes to cholinergic anti-inflammation, prevents systemic inflammation, and improves survival in sepsis. Bacterial endotoxin induced STAT3 tyrosine phosphorylation in macrophages. Both alpha7 nicotinic receptor (alpha7nAChR) activation and inhibition of JAK2 blunt STAT3 phosphorylation. Inhibition of STAT3 phosphorylation mimicked the alpha7nAChR signaling, inhibiting NF-κB and cytokine production in macrophages. Transfection of macrophages with the dominant-negative mutant STAT3F, to prevent its tyrosine phosphorylation, reduced TNF production but did not prevent the alpha7nAChR signaling. However, inhibition of STAT3 protein expression enhanced cytokine production and abrogated alpha7nAChR signaling. Alpha7nAChR controls TNF production in macrophages through a mechanism that requires STAT3 protein expression, but not its tyrosine phosphorylation. In vivo, inhibition of STAT3 tyrosine phosphorylation by stattic prevented systemic inflammation and improved survival in experimental sepsis. Stattic also prevented the production of late mediators of sepsis and improved survival in established sepsis. These results reveal the immunological implications of tyrosine-unphosphorylated STAT3 in infectious diseases.

The cholinergic anti-inflammatory pathway meets microRNA

“…Nicotine and choline inhibit LPSinduced STAT3 Tyr705 phosphorylation, similar to that reported for JAK2 inhibitor or stattic, a typical inhibitor of STAT3 tyrosine phosphorylation [9,10]. These findings suggest that the cholinergic anti-inflammatory pathway is independent of the STAT3 tyrosine phosphorylation, but it requires STAT3 protein expression, suggesting that unphosphorylated STAT3 (U-STAT3) mediates the anti-inflammatory potential of α7nAChR.…”

“…Recent studies with α7nAChR-knockout mice indicate that nicotine can signal through multiple receptors, but choline is a specific α7nAChR agonist [9]. Nicotine and choline inhibit LPSinduced STAT3 Tyr705 phosphorylation, similar to that reported for JAK2 inhibitor or stattic, a typical inhibitor of STAT3 tyrosine phosphorylation [9,10].…”

“…Likewise, nicotine inhibits the NF-κB pathway via STAT3 but independently of the traditional STAT3 transcriptional modulation [8,9]. Despite controversy on the STAT3 phosphorylation, all the studies indicate that STAT3 protein expression is critical for the cholinergic inhibition of the NF-κB pathway [8][9][10]. The role of STAT3 in the cholinergic anti-inflammatory pathway was first shown in postoperative paralytic ileus, a common postsurgical pathology characterized by the inflammation of the intestinal muscularis.…”

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…In addition, we plan to determine whether SOCS1 modulates antimicrobial effector functions in phagocytes. Both STAT1 and STAT3 are activated by LPS to induce cytokine production (13,61,62). While STAT1 plays a deleterious role in polymicrobial sepsis, deletion of STAT3 in myeloid cells leads to higher mortality in polymicrobial sepsis, and loss of STAT3 is associated with enhanced systemic cytokine production and organ damage (63).…”

Critical Role for Lysine 685 in Gene Expression Mediated by Transcription Factor Unphosphorylated STAT3

“…Therefore, inhibitors that selectively target the acetylation of Lys-685 have the potential to inhibit tumorigenesis. Pena et al (29) reported that STAT3-conditional knock-out mice have an overwhelming susceptibility to sepsis due to loss of the antiinflammatory activity of U-STAT3, providing new insight into the role of U-STAT3 in infectious diseases. Further understanding of the diverse signaling pathways that lead to U-STAT3-dependent gene expression will lead to additional opportunities to evaluate the importance of the acetylation of Lys-685 of U-STAT3 in different physiological and pathological settings.…”