Enhanced high‐mobility group box 1 (HMGB1) modulates regulatory T cells (Treg)/T helper 17 (Th17) balance via toll‐like receptor (TLR)‐4‐interleukin (IL)‐6 pathway in patients with chronic hepatitis B

Summary High‐mobility group box 1 ( HMGB 1) proteins are substantially up‐regulated in acute and chronic hepatitis. However, the immunopathogenic role of HMGB 1 in patients with chronic hepatitis B ( CHB ) has not been elucidated. In this study, using a cohort of 36 CHB patients, we demonstrated a crucial role for HMGB 1 to modulate balance between regulatory T ( T reg) and T helper 17 (Th17) cells via the toll‐like receptor ( TLR )‐4‐interleukin ( IL )‐6 pathway. Serum HMGB 1 levels were dramatically higher in CHB patients and increased along with liver injury, inflammation and fibrosis. Notably, HMGB 1 increased along with decreased T reg/ T h17 cells ratios in the periphery or intrahepatic microenvironment, which provides a clue for HMGB 1 to favour T h17 responses whereas inhibit T reg responses. For in vitro studies, serum pools were constructed with serum from CHB patients at an advanced stage, whereas peripheral blood mononuclear cells ( PBMC ) pools were constructed with cells from those at an early stage. CHB ‐serum significantly enhanced retinoic acid‐related orphan receptor‐γt ( ROR γt), whereas they inhibited forkhead box P 3 ( F oxp3) expression in CHB ‐ PBMC , which could be reversed by blocking of HMGB 1, TLR 4, or IL ‐6. Besides, recombinant HMGB 1 ( rHMGB 1) dose‐dependently up‐regulated ROR γt whereas down‐regulated F oxp3 expression in CHB‐PBMC , and meanwhile, rHMGB 1 enhanced TLR 4 and IL ‐6 expression in CHB‐PBMC . Moreover, the axis of HMGB 1– TLR 4‐ IL ‐6– T reg/ T h17 required noncontact interactions between CD 4 and non‐ CD 4 cells. In addition, rHMGB 1 down‐regulated anti‐inflammatory proteins on CD 4 + CD 25 + cells whereas up‐regulated pro‐inflammatory cytokines in CD 4 + CD 25 − cells. In summary, enriched HMGB 1 in CHB patients shifts T reg/ T h17 balance to T h17 dominance via the TLR 4‐ IL ‐6 pathway, which exacerbates liver injury and inflammation.