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Abstract
BackgroundFibrotic 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 α2-antiplasmin (α2AP) 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 α2AP on the development of fibrosis.MethodsTo clarify the mechanism underlying the production of α2AP 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 α2AP on the development of fibrosis.ResultsWe found that HMGB1 induced the production of α2AP 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 α2AP 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 α2AP production, and that the inhibition of HMGB1 and RAGE attenuated these effects in fibroblasts. Furthermore, the blockade of IL-4 signaling by IL-4Rα neutralizing antibodies attenuated the progression of fibrosis and the production of α2AP and HMGB1 in the bleomycin-induced mice.ConclusionThese findings suggest that alternatively activated macrophage-derived HMGB1 induced the production of α2AP through RAGE and that these effects are associated with the development of fibrosis. Our findings may provide a clinical strategy for managing fibrotic disorders.
Highlights
Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring due to excessive production, deposition, and contraction of the extracellular matrix (ECM)
Kanno et al Arthritis Research & Therapy (2020) 22:76 (Continued from previous page). These findings suggest that alternatively activated macrophage-derived high-mobility group box 1 (HMGB1) induced the production of α2AP through receptor for advanced glycation end products (RAGE) and that these effects are associated with the development of fibrosis
We showed that the expression of α2AP is elevated in fibrotic tissue [11, 23,24,25], and α2AP induces the transforming growth factor-β (TGF-β) production through adipose triglyceride lipase (ATGL), which has been described as a member of the calcium-independent phospholipase A2/nutrin/patatin-like phospholipase domain-contain 2 (PNPLA2) family, and is associated with pro-fibrotic effects, such as cytokine production, myofibroblast differentiation, and ECM production [11, 26]. α2AP inhibits the activity of plasmin, which can directly and indirectly degrade a number of matrix proteins by activating latent metalloproteinases (MMPs) [8] and activate hepatocyte growth factor (HGF) [27, 28]
Summary
Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring due to excessive production, deposition, and contraction of the extracellular matrix (ECM) This process usually occurs over many months and years, and can lead to organ dysfunction or death. We showed that the expression of α2AP is elevated in fibrotic tissue [11, 23,24,25], and α2AP induces the transforming growth factor-β (TGF-β) production through adipose triglyceride lipase (ATGL), which has been described as a member of the calcium-independent phospholipase A2 (iPLA2)/nutrin/patatin-like phospholipase domain-contain 2 (PNPLA2) family, and is associated with pro-fibrotic effects, such as cytokine production, myofibroblast differentiation, and ECM production [11, 26]. Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring because of the excessive production, deposition, and contraction of the extracellular matrix (ECM). We examined the mechanism underlying the production of α2AP on the development of fibrosis
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