Table 1.
Regulation of Th17 differentiation.
| Regulatory levels | Regulatory factors | Regulatory mechanism | Ref |
|---|---|---|---|
| Gut microbiota and its metabolites | SFB | Activates DCs to mediate Th17 cell differentiation Stimulates epithelial cells to secrete SAA protein, cooperates with STAT3-activating cytokines, and mediates Th17 cell differentiation |
(29) |
| AIEC | Sensitizes Th17 cells to produce IL-17 | (30) | |
| ETBF | Regulates Th17-cell differentiation via miR-149-3p | (31) | |
| Actinobacterium Eggerthella lenta | Induces intestinal Th17 activation via cardiac glycoside reductase 2 (Cgr2) enzyme | (32) | |
| C. albicans | Promotes the secretion of IgG1 and IL-6 from B cells via TLR2 activation | (33) | |
| S. aureus | Sensitizes Th17 cells to produce IL-17 | (34) | |
| ETBF | Downregulates miR-149-3p and facilitates Th17 cell differentiation | (31) | |
| miR-21 | Promotes Th17 cell development by targeting and inhibiting SMAD-7 | (35) | |
| miR-10a | Inhibits Th17 cells in the gut via IL-12/IL-23p40 signaling pathway | (35) | |
| LPS | Induces Th17 cell differentiation | (36) | |
| ATP | Activates CD70highCD11clow lamina propria cells via P2X and P2Y receptors, thus enhancing the secretion of IL-1β, IL-6 and IL-23 and promoting Th17 cell development | (37) | |
| FICZ | Upregulates IL-17 and IL-22 production | (38) | |
| ITE | Induces Tregs | (38) | |
| SCFAs | Inhibits IL-17 expression and promotes Foxp3 gene expression | (39, 40) | |
| 3-oxoLCA | Inhibits Th17 cell differentiation by directly binding to RORγt | (41, 42) | |
| isoalloLCA | Increases Foxp3 expression by producing mROS, resulting in promoting Treg cell differention | (41, 42) | |
| Metabolic pathway | Polyamine metabolism | Spermidine, a metabolite of polyamine metabolism, is the basis of faithful Th lineage commitment as a substrate for eIF5A hypination | (43) |
| Lipid oxidative metabolism | High-fat diet promotes Th17 cell differentiation and similar to acetyl-CoA carboxylase | (44) | |
| Glycolytic programs | Regulates Th17 differentiation through the transcription factor HIF1α/mTOR signaling pathway | (45) | |
| Lactate | Inhibits the proliferation of Th17 cells and increases IL-17A expression | (46) | |
| Cytokines | IL-6 | Activates JAK2-STAT3 signaling pathway, upregulates the expression of RORγt gene and promotes Th17 cell differentiation | (47) |
| TGF-β | Activates Smad2 signaling pathway, promotes Th17 cell differentiation and promotes the emergence of IL-22-producing | (48) | |
| IL-23 | Promotes Th17 cell differentiation and is a key factor perpetuating Th17 cell activation and cytokine production | (49) | |
| IL-21 | Promotes the differentiation of Th17 cells and increases expression and secretion of IL-17A and IL-22 by upregulating RORγt expression, and inhibits Tregs differentiation by downregulating Foxp3 expression | (50) | |
| IL-1β | Promotes Th17 polarization via the IL1R/PI3K-mTOR signaling pathway | (51) | |
| Transcription factors | STAT3 | Binds to the promoter of IL-17 and directly controls the expression of the transcription factor RORγt for Th17 differentiation transcription factors | (52) |
| RORγt | Promotes IL-17 gene transcription by directly binding to the IL-17 gene promoter | (47) | |
| IRF4 | Promotes Th17 cell differentiation by interacting with BATF–JUN heterodimers to bind to AICEs or cooperating with the transcription factor STAT3 | (53) | |
| BATF | BATF knockout inhibits the differentiation of T helper Th17 cells | (54) | |
| JunB | In collaboration with basic leucine zipper BATF, regulates the expression of Th17-related genes | (55) | |
| HIF-1 | Transcribes and activates RORγt, and promotes Th17 cell development when recruitment to the IL-17 promoter via tertiary complex formation with p300 and RORγt | (56) | |
| Toll-like receptors | TLR2 | Causes STAT3 phosphorylation | (57) |
| TLR3 | Induces DC cells to produce IL-23 and synthesis of IL-17A and IL-21 | (58) | |
| TLR4 | Promotes Th17 differentiation by downregulating the expression of miR-30a, activating RelA | (59) | |
| TLR7 | Inhibits Th17 cell differentiation and IL-17 production in established Th17 cells | (60) | |
| TLR8 | Mediates the expression of IL-23 in neutrophils | (61) |