Regulation of Inflammation by IL-17A and IL-17F Modulates Non-Alcoholic Fatty Liver Disease Pathogenesis

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. While it is well-accepted that inflammation is central to NAFLD pathogenesis, the immune pathway(s) orchestrating disease progression are poorly defined. Notably, IL-17RA signaling, via IL-17A, plays an important role in obesity-driven NAFLD pathogenesis. However, the role of the IL-17F, another IL-17RA ligand, in NAFLD pathogenesis has not been examined. Further, the cell types expressing IL-17RA and producing IL-17RA ligands in the pathogenesis of NAFLD have not been defined. Here, IL-17RA-/-, IL-17A-/-, IL-17F-/- and wild-type (WT) mice were fed either standard chow diet or methionine and choline deficient diet (MCDD)—a diet known to induce steatosis and hepatic inflammation through beta-oxidation dysfunction—and hepatic inflammation and NAFLD progression were subsequently quantified. MCDD feeding augmented hepatic IL-17RA expression and significantly increased hepatic infiltration of macrophages and IL-17A and IL-17F producing CD4+ and CD8+ T cells in WT mice. In contrast, IL-17RA-/-, IL-17A-/-, and IL-17F-/- mice, despite increased steatosis, exhibited significant protection from hepatocellular damage compared to WT controls. Protection from hepatocellular damage correlated with decreased levels of hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators associated with NAFLD. In sum, our results indicate that the IL-17 axis also plays a role in a MCDD-induced model of NAFLD pathogenesis. Further, we show for the first time that IL-17F, and not only IL-17A, plays an important role in NAFLD driven inflammation.

Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice

“…RNA was extracted from lysed tissue samples, and cDNA was transcribed according to previously described protocol [23], [24]. qPCR analysis was then completed utilizing a Light Cycler 480 II (Roche), Sybr Green I Master mix (Roche) and the following primers pairs: Abca1 For GCTGCAGGAATCCAGAGAAT Rev CATGCACAAGGTCCTGAGAA; Mmp2 For GATGGCATTCCAGGAGTCTG Rev CCAGCAAGTAGATGCTGCCT; Rag1 For CTGAAGCTCAGGGTAGACGG Rev CAACCAAGCTGCAGACATTC; Sox13 For ACTGCTCTCTGGTGAGGCAC Rev GTCTGAGGAGAAGAAGGAGCC; F4/80 For CTTTGGCTATGGGCTTCCAGTC Rev GCAAGGAGGACAGAGTTTATCGTG; Ccl2 For AGATGCAGTTAACGCCCCAC Rev TGTCTGGACCCATTCCTTCTTG; Ccr2 For CCACTGTCTTTGAGGCTTGTTG Rev GCTCTACATTCACTCCTTCCACTG; IFNγ For TGGCTGTTTCTGGCTGTTACTG Rev ACGCTTATGTTGTTGCTGATGG Arg1 For GTGGCAGAGGTCCAGAAGAATG Rev TTGTCAGGGGAGTGTTGATGTC; iNOS For GTTCTCAGCCCAACAATACAAGA Rev GTGGACGGGTCGATGTCAC; F4/80 For CCCCAGTGTCCTTACAGAGTG Rev GTGCCCAGAGTGGATGTCT; CD4 For TCCTTCCCACTCAACTTTGC Rev AAGCGAGACCTGGGGTATCT; Tbet For AGCAAGGACGGCGAATGTT Rev GGGTGGACATATAAGCGGTTC; IL6 For CCAAGAGGTGAGTGCTTCCC Rev CTGTTGTTCAGACTCTCTCCCT; TNF For ATGAGCACAGAAAGCATGATCCGC Rev CCAAAGTAGACCTGCCCGGACTC; Beta Actin For GGCCCAGAGCAAGAGAGGTA Rev GGTTGGCCTTAGGTTTCAGG.…”

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

“…IL-6 expressed in hepatocytes, and its level in the blood, correlates positively with the degree of liver inflammation, and fibrosis (46). Another key cytokine in NAFLD is interleukin-17 (IL-17) (41). The activation of the IL-17 axis has shown to have a central role in the progression from NAFLD to NASH in experimental studies (15, 24, 41, 42).…”

“…Another key cytokine in NAFLD is interleukin-17 (IL-17) (41). The activation of the IL-17 axis has shown to have a central role in the progression from NAFLD to NASH in experimental studies (15, 24, 41, 42). The role of IL-17 family cytokines will be discussed further elsewhere in this paper.…”

“…Th17 cells secrete the IL-17, IL-21, and e IL-22, being important in immunity against extracellular infectious agents such as bacteria and fungi but also contribute in the immunopathogenesis of many diseases such as psoriasis and tumors (51, 91–93). IL-17 is the most studied Th17-secreted cytokine in liver disease (15, 41, 42). The differentiation of Treg, the functional counterpart of Th17 cells, has the TGF-β as a pivotal factor in the presence of retinoic acid (94–97).…”

Serum Concentrations of Th17-Associated Interleukins and Autoimmune Phenomena are Associated with the Degree of Liver Damage in Alcoholic Liver Disease

“…Stimulation of mice hepatocytes, HSCs and Kupffer cells (KCs) with IL-17F had similar to IL-17A, but less pronounced proinflammatory and profibrotic effects upregulating the expression of IL-6, IL-β1, TGF-β and TNF-α mRNA [35]. The research on animal models suggested involvement of both IL-17F and IL-17A in the pathogenesis of NASH, as the activation of IL-17RA by both interleukins was required for NASH progression [36].…”