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Systemic high-mobility group box 1 administration suppresses skin inflammation by inducing an accumulation of PDGFR?(+) mesenchymal cells from bone marrow.

ABSTRACT: High-mobility group box 1 (HMGB1) mobilizes platelet-derived growth factor receptor alpha-positive (PDGFR?(+)) mesenchymal cells from bone marrow (BM) into circulation. However, whether HMGB1-induced endogenous PDGFR?(+) mesenchymal cells stimulate skin regeneration has been unclear. Here, we investigated the functions of the HMGB1/BM-PDGFR?(+) mesenchymal cell axis in the regeneration of mouse skin grafts. We found that intravenous HMGB1 administration induced an accumulation of endogenous BM-PDGFR?(+) mesenchymal cells followed by significant inflammatory suppression in the grafts. In contrast, mice with reduced BM-PDGFR?(+) mesenchymal cells showed massive inflammation of the grafts compared to mice that had normal levels of these cells even after HMGB1 administration, suggesting that BM-PDGFR?(+) mesenchymal cells contribute to the HMGB1-induced anti-inflammatory effect. We also found that intravenously administered HMGB1 augmented the local migration of BM-PDGFR?(+) mesenchymal cells from circulation to skin graft by inducing the expression of CXCR4, an SDF-1 receptor, on these cells. Finally, we showed the therapeutic activity of the HMGB1/BM-PDGFR?(+) mesenchymal cell axis in an allergic contact dermatitis model. The results illustrated the contribution of the HMGB1/BM-PDGFR?(+) mesenchymal cell axis in suppressing the inflammation of injured/inflamed skin. These findings may provide future perspectives on the use of HMGB1-based medicines for intractable diseases.

SUBMITTER: Aikawa E

PROVIDER: S-EPMC4457135 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Systemic high-mobility group box 1 administration suppresses skin inflammation by inducing an accumulation of PDGFRα(+) mesenchymal cells from bone marrow.

Aikawa Eriko E Fujita Ryo R Kikuchi Yasushi Y Kaneda Yasufumi Y Tamai Katsuto K

Scientific reports 20150605

High-mobility group box 1 (HMGB1) mobilizes platelet-derived growth factor receptor alpha-positive (PDGFRα(+)) mesenchymal cells from bone marrow (BM) into circulation. However, whether HMGB1-induced endogenous PDGFRα(+) mesenchymal cells stimulate skin regeneration has been unclear. Here, we investigated the functions of the HMGB1/BM-PDGFRα(+) mesenchymal cell axis in the regeneration of mouse skin grafts. We found that intravenous HMGB1 administration induced an accumulation of endogenous BM-P ...[more]

PMID: 26046579

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Project description:Myeloid-derived suppressor cells are immune-suppressive cells that are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. As myeloid-derived suppressor cells inhibit anti-tumor immunity and promote tumor progression, we are determining how their viability is regulated. Previous studies have established that the damage-associated molecular pattern molecule high-mobility group box protein 1 drives myeloid-derived suppressor cell accumulation and suppressive potency and is ubiquitously present in the tumor microenvironment. As high-mobility group box protein 1 also facilitates tumor cell survival by inducing autophagy, we sought to determine if high-mobility group box protein 1 regulates myeloid-derived suppressor cell survival through induction of autophagy. Inhibition of autophagy increased the quantity of apoptotic myeloid-derived suppressor cells, demonstrating that autophagy extends the survival and increases the viability of myeloid-derived suppressor cells. Inhibition of high-mobility group box protein 1 similarly increased the level of apoptotic myeloid-derived suppressor cells and reduced myeloid-derived suppressor cell autophagy, demonstrating that in addition to inducing the accumulation of myeloid-derived suppressor cells, high-mobility group box protein 1 sustains myeloid-derived suppressor cell viability. Circulating myeloid-derived suppressor cells have a default autophagic phenotype, and tumor-infiltrating myeloid-derived suppressor cells are more autophagic, consistent with the concept that inflammatory and hypoxic conditions within the microenvironment of solid tumors contribute to tumor progression by enhancing immune-suppressive myeloid-derived suppressor cells. Overall, these results demonstrate that in addition to previously recognized protumor effects, high-mobility group box protein 1 contributes to tumor progression by increasing myeloid-derived suppressor cell viability by driving them into a proautophagic state.

Dataset Information

Systemic high-mobility group box 1 administration suppresses skin inflammation by inducing an accumulation of PDGFR?(+) mesenchymal cells from bone marrow.

Publications

Systemic high-mobility group box 1 administration suppresses skin inflammation by inducing an accumulation of PDGFRα(+) mesenchymal cells from bone marrow.

Similar Datasets

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