The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis

Abstract

Oxidative stress is a key feature in both chronic inflammation and cancer. P38 regulated/activated protein kinase (PRAK) deficiency can cause functional disorders in neutrophils and macrophages under high oxidative stress, but the precise mechanisms by which PRAK regulates reactive oxygen species (ROS) elimination and its potential impact on CD4+ T helper subset function are unclear. The present study reveals that the PRAK-NF-E2-related factor 2(NRF2) axis is essential for maintaining the intracellular redox homeostasis of T helper 17(Th17) cells, thereby promoting Th17 cell differentiation and antitumor effects. Through mechanistic analysis, we identify NRF2 as a novel protein substrate of PRAK and find that PRAK enhances the stability of the NRF2 protein through phosphorylation NRF2 Serine(S) 558 independent of protein ubiquitination. High accumulation of cellular ROS caused by loss of PRAK disrupts both glycolysis and PKM2-dependent phosphorylation of STAT3, which subsequently impairs the differentiation of Th17 cells. As a result, Prak knockout (KO) mice display significant resistance to experimental autoimmune encephalomyelitis (EAE) but impaired antitumor immunity in a MC38 tumor model. This work reveals that the PRAK-NRF2-mediated antioxidant pathway is a metabolic checkpoint that controls Th17-cell glycolysis and differentiation. Targeting PRAK is a promising strategy for maintaining an active ROS scavenging system and may lead to potent Th17 cell antitumor immunity.

IL-6/gp130 signaling in CD4 + T cells drives the pathogenesis of pulmonary hypertension

“…S10 I ). Because Th17 cells are characterized by distinctive homeostasis involving the upregulation of glycolysis ( 27 – 29 ), we focused on the metabolic genes associated with respiratory functions. Numerous glycolysis-related gene expressions exhibited downregulation in Il6 KO rats, whereas the majority of TCA cycle gene expressions remain unaffected ( Fig.…”

“…In the present study, IL-21 + cells around pulmonary vessels, which resulted in remodeling in the SuHx model in WT rats, were rarely seen in Il6 KO rats. mRNA levels of genes involved in glycolysis, which is enhanced during differentiation of Th17 cells ( 27 – 29 ), were up-regulated in an IL-6-dependent manner in CD4 + cells of the SuHx lungs. Taken together, these results suggest that activation of AHR triggers a positive feedback loop of Th17 cell differentiation via the IL-6/AHR signaling axis in PAH.…”

Impact of albumin–lymphocyte–platelet–C‐reactive protein index as a prognostic indicator of hepatocellular carcinoma after resection: Associated with nuclear factor erythroid 2–related factor 2

“…22 The Nrf2 promoted the differentiation of T helper 17 cells. 23 T helper 17 cells promoted inflammatory responses through interleukin-17. 24 The association between p-Nrf2 and the tumor microenvironment and the relationship between tumor-infiltrating T cells and peripheral blood lymphocytes has been reported.…”

The Role of Oxidative Stress in Tumorigenesis and Progression

“…Furthermore, ROS indirectly induces an antitumor effect by boosting immune cells. For example, PRAK deficiency-induced ROS accumulation impairs the differentiation of Th17 cells and antitumor immunity though disrupting phosphorylation of STAT3 [ 57 ]. ROS spurs dendritic cell maturation by activating p38-MAPK and ERK1/2 [ 58 ].…”

“…For example, tumor-associated neutrophils produce O 2 • mediated by NOX2, inhibiting the expansion of γδ T cells, which promote tumor development by producing IL-17 [ 81 ]. Recent studies have indicated that the PRAK-NRF2 axis, which is associated with ROS, is essential for Th17 cells to maintain antitumor effects [ 57 ]. Phosphatase PAC1, as an oxidative stress responder [ 82 ] and a negative regulator of the immune system, specifically inhibits T lymphocyte defense and promotes tumor immune escape [ 83 ].…”