Innate sensing of microbial products promotes wound-induced skin cancer

Nat Commun. 2015 Jan 9;6:5932. doi: 10.1038/ncomms6932.

Abstract

The association between tissue damage, chronic inflammation and cancer is well known. However, the underlying mechanisms are unclear. Here we characterize a mouse model in which constitutive epidermal extracellular-signal-regulated kinase-MAP-kinase signalling results in epidermal inflammation, and skin wounding induces tumours. We show that tumour incidence correlates with wound size and inflammatory infiltrate. Ablation of tumour necrosis factor receptor (TNFR)-1/-2, Myeloid Differentiation primary response gene 88 or Toll-like receptor (TLR)-5, the bacterial flagellin receptor, but not other innate immune sensors, in radiosensitive leukocytes protects against tumour formation. Antibiotic treatment inhibits, whereas injection of flagellin induces, tumours in a TLR-5-dependent manner. TLR-5 is also involved in chemical-induced skin carcinogenesis in wild-type mice. Leukocytic TLR-5 signalling mediates upregulation of the alarmin HMGB1 (High Mobility Group Box 1) in wound-induced papillomas. HMGB1 is elevated in tumours of patients with Recessive Dystrophic Epidermolysis Bullosa, a disease characterized by chronic skin damage. We conclude that in our experimental model the combination of bacteria, chronic inflammation and wounding cooperate to trigger skin cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry
  • Crosses, Genetic
  • Disease Models, Animal
  • Female
  • Flagellin / metabolism
  • HMGB1 Protein / metabolism*
  • Hematopoiesis
  • Humans
  • Inflammation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / metabolism
  • Signal Transduction
  • Skin / pathology
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / microbiology*
  • Toll-Like Receptor 5 / metabolism
  • Wounds and Injuries / pathology

Substances

  • Anti-Bacterial Agents
  • HMGB1 Protein
  • HMGB1 protein, human
  • HMGB1 protein, mouse
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • TLR5 protein, human
  • Toll-Like Receptor 5
  • Flagellin