Deeper insight into the role of IL-17 in the relationship beween hypertension and intestinal physiology

Abstract

With the incidence of hypertension increasing worldwide, more and more the mechanisms of hypertension from the perspective of immunity have found. Intestinal microbiota as well as its metabolites relationship with hypertension has attracted great attention from both clinicians and investigators. However, the associations of hypertension with lesions of a large number of immune factors including IL-17, MCP-1, IL-6, TGF-β, IL-10 and others have not been fully characterized. In this review, after introducing the immune factors as the most potent anti/pro-hypertension agents known, we provide detailed descriptions of the IL-17 involved in the pathology of hypertension, pointing out the underlying mechanisms and suggesting the clinical indications.

Keywords: Gut microbiota; Hypertension; IL-10; IL-17; IL-6; Immune factors; MCP-1; TGF-β.

Fig. 1

Diagram of the generation of Th17 cells and the association with other factors. While TCR is activated, TGF-β and IL-6 activate transcription factors Smads and STAT3 and induce the expression of ROR, so that naive T cells differentiate to Th17, which secretes IL-21 and in turn promotes the process in a positive feedback manner continually. IL-17 inhibits the production of CXCL9/10 from tumor cells, thus stop CD8⁺ CTLs and Tregs from infiltrating tumor cells

Fig. 2

Model diagram of the regulatory of IL-17 between gut and hypertension. SCFAs can inhibit HDAC in T cells, which promotes the acetylation of kinase p70 S6 and phosphorylated rS6, thus promoting the mTOR pathway necessary for the proliferation of Th17 cells. HSD could activate the p38/MAPK pathway, involving TonEBP/NFAT5 SGK1 and subsequently mediate the secretion of IL-17a by naive CD4⁺ cells. Moreover, L.murinus can prevent production of Th17 cells induced by HSD. Th17 cells are also mediated by SFB through ROS and SAA. Then IL-17 can promote the reabsorbtion of salt/water and inhibit NO-derived from eNOS, consequently lead to elevation of blood pressure

Fig. 3

Correlation pattern of MCP-1, IL-6, TGF-β and IL-10 between gut and hypertension. a ATP can promote the secretion of TGF-β by immune cells and DC in different ways, and TGF-β could further drive the differentiation of Th17 cells. However, TGF-β has an inverse effect at high concentrations b Th17 cells can be inhibited by IL-10 in an APC-depended way. IL-10 is secreted by several cells like immune or myeloid and mediated by gut microbiota and metabolism. c IL-6 can be produced by LPS-stimulated IEC and involved in hypertension induced by AngII. d SCFAs can inhibit the expression of MCP-1, which promotes the aggregation of monocytes as well as Mφ and lead to a lower elasticity of vascular wall. Monocytes and Mφ also produce proinflammatory cytokines that induce the secretion of MCP-1 and thus form a positive feedback loop. Additionally, IL-17 induces MCP-1 production in PI3K, JNK, ERK pathways