Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-κB activation

TLDR

Tissue damage triggers healing by recruiting differentiated and stem cells, with soluble factors such as HMGB1 and SDF‑1/CXCL12 guiding mesoangioblasts and fibroblasts toward the injury site. HMGB1 activates NF‑κB through ERK phosphorylation, and NF‑κB signaling is required for chemotaxis toward HMGB1 and SDF‑1/CXCL12 as well as for efficient mesoangioblast infiltration in dystrophic mice, indicating a role for NF‑κB in tissue regeneration beyond inflammation.

Abstract

Tissue damage is usually followed by healing, as both differentiated and stem cells migrate to replace dead or damaged cells. Mesoangioblasts (vessel-associated stem cells that can repair muscles) and fibroblasts migrate toward soluble factors released by damaged tissue. Two such factors are high mobility group box 1 (HMGB1), a nuclear protein that is released by cells undergoing unscheduled death (necrosis) but not by apoptotic cells, and stromal derived factor (SDF)–1/CXCL12. We find that HMGB1 activates the canonical nuclear factor κB (NF-κB) pathway via extracellular signal-regulated kinase phosphorylation. NF-κB signaling is necessary for chemotaxis toward HMGB1 and SDF-1/CXCL12, but not toward growth factor platelet-derived growth factor, formyl-met-leu-phe (a peptide that mimics bacterial invasion), or the archetypal NF-κB–activating signal tumor necrosis factor α. In dystrophic mice, mesoangioblasts injected into the general circulation ingress inefficiently into muscles if their NF-κB signaling pathway is disabled. These findings suggest that NF-κB signaling controls tissue regeneration in addition to early events in inflammation.