Alternatively activated macrophages are associated with the alpha2AP production that occurs with the development of dermal fibrosis : The role of alternatively activated macrophages on the development of fibrosis.

BACKGROUND: Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring because of the excessive production, deposition, and contraction of the extracellular matrix (ECM). However, the detailed mechanisms underlying these disorders remain unclear. It was recently reported that alpha2-antiplasmin (alpha2AP) is elevated in fibrotic tissue and that it is associated with the development of fibrosis. In the present study, we examined the mechanism underlying the production of alpha2AP on the development of fibrosis. METHODS: To clarify the mechanism underlying the production of alpha2AP on the development of fibrosis, we focused on high-mobility group box 1 (HMGB1), which is associated with the development of fibrosis. The mouse model of bleomycin-induced fibrosis was used to evaluate the production of alpha2AP on the development of fibrosis. RESULTS: We found that HMGB1 induced the production of alpha2AP through receptor for advanced glycation end products (RAGE) in fibroblasts. Next, we showed that macrophage reduction by a macrophage-depleting agent, clodronate, attenuated the progression of fibrosis and the production of alpha2AP and HMGB1 in the bleomycin-induced mice. We also showed that IL-4-stimulated alternatively activated macrophages induced the production of HMGB1, that IL-4-stimulated alternatively activated macrophage conditioned media (CM) induced pro-fibrotic changes and alpha2AP production, and that the inhibition of HMGB1 and RAGE attenuated these effects in fibroblasts. Furthermore, the blockade of IL-4 signaling by IL-4Ralpha neutralizing antibodies attenuated the progression of fibrosis and the production of alpha2AP and HMGB1 in the bleomycin-induced mice. CONCLUSION: These findings suggest that alternatively activated macrophage-derived HMGB1 induced the production of alpha2AP through RAGE and that these effects are associated with the development of fibrosis. Our findings may provide a clinical strategy for managing fibrotic disorders.