HMGB1 aggravates lipopolysaccharide-induced acute lung injury through suppressing the activity and function of Tregs.

Background: CD4(+)CD25(+)FoxP3(+) T helper cells (Tregs), a subgroup of CD4(+) T helper cells, are critical effectors that protect against acute lung injury (ALI) by contact-dependent suppression or releasing anti-inflammatory cytokines including interleukin-10 (IL-10), and transforming growth factor (TGF-beta). HMGB1 (High mobility group box 1 protein) was identified as a nuclear non-histone DNA-binding chromosomal protein, which participates in the regulation of lung inflammatory response and pathological processes in ALI. Previous studies have suggested that Tregs overexpresses the HMGB1-recognizing receptor. However, the interaction of HMGB1 with Tregs in ALI is still unclear. Objective: To investigate whether HMGB1 aggravates ALI by suppressing immunosuppressive function of Tregs. Methods: Anti-HMGB1 antibody and recombinant mouse HMGB1 (rHMGB1) were administered in lipopolysaccharide (LPS)-induced ALI mice and polarized LPS-primed Tregs in vitro. The Tregs pre-stimulated with or without rHMGB1 were adoptively transferred to ALI mice and depleted by Diphtheria toxin (DT). For coculture experiment, isolated Tregs were first pre-stimulated with or without rHMGB1 or anti-HMGB1 antibody, then they were cocultured with bone marrow-derived macrophages (BMMs) under LPS stimulation. Results: Tregs protected against acute lung pathological injury. HMGB1 modulated the suppressive function of Tregs as follows: reduction in the number of the cells and the activity of Tregs, the secretion of anti-inflammatory cytokines (IL-10, TGF-beta) from Tregs, the production of IL-2 from CD4(+) T cells and CD11c(+) DCs, and the M2 polarization of macrophages, as well as inducing proinflammatory response of macrophages. Conclusions: HMGB1 could aggravate LPS induced-ALI through suppressing the activity and function of Tregs.