Th17/Treg balance: the bloom and wane in the pathophysiology of sepsis

Abstract

Sepsis is a multi-organ dysfunction characterized by an unregulated host response to infection. It is associated with high morbidity, rapid disease progression, and high mortality. Current therapies mainly focus on symptomatic treatment, such as blood volume supplementation and antibiotic use, but their effectiveness is limited. Th17/Treg balance, based on its inflammatory property, plays a crucial role in determining the direction of the inflammatory response and the regression of organ damage in sepsis patients. This review provides a summary of the changes in T-helper (Th) 17 cell and regulatory T (Treg) cell differentiation and function during sepsis, the heterogeneity of Th17/Treg balance in the inflammatory response, and the relationship between Th17/Treg balance and organ damage. Th17/Treg balance exerts significant control over the bloom and wanes in host inflammatory response throughout sepsis.

Keywords: Th17; Treg; balance; pathophysiology; sepsis.

Figure 1

Cytokines regulate Th17/Treg balance. Naïve T cells can differentiate into Th17 and Tregs in response to specific cytokines. IL-1β, IL-6, IL-21, IL-23 and TGF-β induce Th17 differentiation. IL-6, IL-21 and IL-23 promote STAT3 phosphorylation, induce RORγt gene expression, and then stimulate CD4⁺ T cells to differentiate into Th17. mTOR is activated through the PI3K/Akt pathway to promote Th17 differentiation. A low TGF-β concentration activates SMAD and synergizes with IL-6 to promote Th17 production. Numerous mature Th17 secrete pro-inflammatory factors such as IL-17, IL-21, IL-22, IFN-γ, TNF-α, etc., promoting inflammation. Treg differentiation is mediated by IL-2 and TGF-β. IL-2/STAT5 pathway and high concentrations of TGF-β promote the expression of the Foxp3 gene and contribute to Treg differentiation. PI3K/Akt/mTOR pathway inhibits the expression of Foxp3 to suppress Treg differentiation. AMPK inhibits mTOR activity and promotes Foxp3 expression, which facilitates Treg differentiation. Many Tregs secrete IL-10 and TGF-β and induce host anti-inflammatory responses. Th17, T helper 17; Treg, regulatory T; IL, interleukin; TGF-β, transforming growth factor-β; TCR, T cell receptor; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; STAT3, signal transducer and activator of transcription 3; STAT5, signal transducer and activator of transcription 5; mTOR, mammalian target of rapamycin; RORγt, retinoid acid-related orphan receptor γt; HIF-1α, hypoxia inducible factor 1α; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; Foxp3, forkhead box protein P3; AMPK, AMP-activated protein kinase.