Bose, Purabi Deka, Bose, Moumita, Bose, Sujoy, Nayak, Flora, Das, Snigdha Jyoti, Kashyap, Natasha, and Saikia, Anjan Kumar
Background/Aims Role of specific chemokine-chemokine receptor(s) axis involvement has been increasingly realized in many pathophysiological conditions involving inflammatory states, including sporadic reports in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The present study aimed to evaluate the significance of chemokine RANTES and associated immunomodulation and modulations of key HSC signaling regulators in the susceptibility and severity of NAFLD in non-obese subjects. Methods Clinically characterized NAFLD cases (n=58; NAFL, 45; nonalcoholic steatohepatitis [NASH], 13) with clinical details and fibroscan based liver stiffness measurement (LSM)-score were enrolled along with healthy controls (HC, n=90). Serum RANTES and cytokine panels were evaluated by enzyme-linked immunosorbent assay. Chemokine receptors (CCR5, CCR1), monocyte (sCD14, mCD14) and its activation (CD40, HLA-DR), T-cell activation (CD25) profile were analyzed using various molecular tools. All statistical analysis was performed using SPSS version 13.0 software. Results The serum RANTES levels were significantly higher in NASH cases compared to NAFL cases (p=0.29) and HC subjects (p=0.047). Expression of RANTES (CCL5) ligands CCR5 and CCR1 mRNA and cellular protein expression was increased in NASH cases compared to both HC and NAFL cases. Both significant monocyte and T-cell activation profile was observed in NASH compared to NAFL cases and HC cases, and nonsignificantly increased in NAFL cases compared to HC subjects. A sharp Th1 biased cytokine profile with upregulation of tumor necrosis factor (TNF)-α , interleukin (IL)-12 and IL-2 was observed in NASH cases compared to NAFL cases. The profile of regulators of HSC activations viz., TNF-α, transforming growth factor-β1, PDGF-BB and vascular endothelial growth factor was significantly activated in NAFLD cases, and correlated positively with serum RANTES expression, monocyte activation markers (CD40 and CCR5), higher alanine transaminase, GGTP, and LSM-score. Conclusions RANTES levels possibly contributes to chronic inflammatory microenvironment in NAFL subjects through increased immunomodulation and increased expression of regulators associated with HSC activation in non-obese NAFL cases thereby augmenting progression to NASH. Therefore RANTES-chemokine receptor axis therefore holds both prognostic and therapeutic importance in NAFLD. [ABSTRACT FROM AUTHOR]