IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell–iTreg cell balance

Abstract

Interleukin 17 (IL-17)-producing helper (TH17) and inducible regulatory CD4+ T (iTreg) cells emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce iTreg cell development while potently inhibiting TH17 development. Here, we found that IL-1 was required to fully override RA-mediated Foxp3 expression and induce protective TH17 responses. Through induction of an NF-κB-dependent repression of SOCS3 expression, IL-1 increased the amplitude and duration of STAT3 phosphorylation induced by TH17-polarizing cytokines, leading to an altered balance of STAT3–STAT5 binding to shared consensus sequences in developing T cells. Thus, IL-1 signaling differentially modulated STAT activation downstream of cytokine receptors to control TH17–iTreg developmental fate.

Deciphering the crosstalk among IL-1 and IL-10 family cytokines in intestinal immunity

“…Experiments have shown that the addition of IL-1b to Tregs results in the loss of Treg cellular identity and differentiation into IL-17-producing TH17 cells. One possible mechanism may be the effects of IL-1b on the production of retinoic acid, a key signaling molecule that can modulate Treg development through the Stat3 pathway [86]. In contrast to the effects of IL-1b on Treg differentiation, a new study has identified IL-33 to have a positive role in the differentiation and maintenance of Tregs.…”

IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity

“…It has been reported that IRAK1 directly phosphorylates STAT3 in T cells cultured with TGF-b and IL-6 (16), yet we found that in the presence of IL-23, IRAK1 signaling acts downstream of IL-1b to promote sustained IL-17 production. It was shown recently that IL-1 additionally promotes STAT3 tyrosine phosphorylation induced by IL-23 by repressing suppressor of cytokine signaling 3, a negative regulator of the STAT3 pathway (22). In line with our finding that IRAK1 signaling is not required for upregulation of RORgt expression by IL-1b, it was shown that lack of MyD88 in CD4 + T cells impairs Th17 cell generation without affecting RORgt expression (23 the MyD88-mediated activation of the mTOR signaling pathway by IL-1b promotes IL-23R induction and sustains IL-17 production.…”

The Neonatal Methylome as a Gatekeeper in the Trajectory to Childhood Asthma

“…Indeed, in neonates who became asthmatic by age 9, SMAD3 promoter hypermethylation, an epigenetic configuration consistent with low SMAD3 expression, was strongly associated with high IL-1β production. This convergence may destabilize the T regulatory cell program, enhance inflammation, and promote Th17 differentiation [27], ultimately favoring the development of asthma. While it is unclear whether these mechanisms operate pre-and/or perinatally, detection of the relationship between SMAD3 methylation and IL-1β production selectively among children of asthmatic mothers implies that the in utero environment is critical for directing the epigenetic trajectory towards childhood asthma.…”