collagen

Increased deposition and remodeling of collagen in the microenvironment of tissues and tumors depend on chronic inflammation, a leading factor addressing cancer establishment and evolution. However, even minor changes in immune activation inside a tissue can induce structural remodeling if persisting. Reciprocally, collagen accumulation can affect the local immunity e.g. by interaction with LAIR-1 receptor on immune cells. We have shown the gut colonization of germ-free (GF) mice with intestinal microflora from conventional mice (CV) quickly modifies the mucosal scaffold and influences the systemic immunity. In vivo in rat, the induction of either chronic colitis (dextran sodium sulphate – DSS) or colon carcinogenesis (azoxymethane – AOM) resulted to sustain persistent inflammation and remodeling of the collagen scaffold organization, even when the mucosa appears recovered, at one month after acute induction. The collagen scaffold remodeling associated to persistent pro-inflammatory cytokine activities was documented by multi-photon confocal microscopy (second harmonic generation). This was found both after bacterial (GF CV) and chemical (DSS or AOM) stimulations, making the structural changes mirroring the microenvironment immunological activation. These results suggest a mucosal “inflammatory threshold (IT)”, i.e. a regulatory limit for tolerating inflammatory signals and maintaining the tissue homeostasis. The collagen scaffold quickly adapts to the immune microenvironment conditions. A dis-balance between pro-inflammatory and regulatory signals can overcome IT even under apparently normal or reduced levels of microenvironmental cytokines, allowing a smoldering inflammation. The scaffold structure alteration can identify either cancer niche or chronic colitis depending on the local cytokine proportions (IL-6, IFN-γ, IL-1, TGF-β). Furthermore, in a mouse pancreatic cancer model different IL-17 expression differently addressed the profibrotic collagen organization. Concluding, cytokine levels and collagen scaffold remodeling measured in the tissue may represent a new diagnostic tool.