Presentation: M2 Monocyte/Macrophage-Derived MMP12 Plays a Pivotal Role in Contact Hypersensitivity ( World Allergy Congress)

Wednesday, 14 October 2015: 13:45 - 14:00

Room R1 ABC (Floor 3) (Coex Convention Center)

Daiki Nakagomi, MD, PhD , Department of Allergy and Clinical Immunology, Chiba University, Chiba, Japan

Kotaro Suzuki, MD, PhD , Department of Allergy and Clinical Immunology, Chiba University, Chiba, Japan

Kazuyuki Meguro, MD, PhD , Department of Allergy and Clinical Immunology, Chiba University, Chiba, Japan

Junichi Hosokawa, MD, PhD , Department of Allergy and Clinical Immunology, Chiba University, Chiba, Japan

Hiroshi Nakajima, MD, PhD , Department of Allergy and Clinical Immunology, Chiba University, Chiba, Japan

Background: Recent studies have suggested that M2 macrophages play key roles in the suppression of Th1 responses and the orchestration of tissue repair; however, the roles of M2 macrophages in contact hypersensitivity (CHS), an animal model of contact dermatitis, remain unknown. The purpose of this study is to determine the roles of M2 monocytes/macrophages in CHS.

Methods: Phenotype of F4/80⁺ cells in the inflammatory sites in DNFB-induced CHS was analyzed. The effects of intradermal transplantation of bone marrow (BM)-derived M2 macrophages on DNFB-induced CHS were examined. Transcriptome profiling of mannose receptor (MR)⁺F4/80⁺ cells in the inflammatory sites of DNFB-induced CHS was analyzed by RNA-sequencing analysis. The role of IL-4-STAT6 signaling in the induction of matrix metalloproteinase 12 (MMP12), one of MR⁺F4/80⁺ cells-related genes, in BM-derived macrophages was assessed. The effect of intradermal injection of recombinant MMP12 on skin inflammation was examined. The roles of MMP12 in DNFB-induced CHS were examined by using MMP12-deficient mice and MMP12 inhibitors.

Results: F4/80⁺cells expressing MR were increased at the sites of CHS. The intradermal transplantation of BM-derived M2 macrophages exacerbated DNFB-induced CHS. Transcriptome analysis revealed that MMP12 was highly and preferentially expressed in MR⁺ F4/80⁺cells at the site of CHS, and IL-4-STAT6 signaling induced MMP12 expression in BM-derived macrophages. Importantly, intradermal injection of recombinant MMP12 induced skin inflammation. DNFB-induced CHS was significantly attenuated in MMP12-deficient mice as compared with that in control mice. Furthermore, topical application of MMP12 inhibitors suppressed DNFB-induced CHS.

Conclusion: MMP12 is produced by M2 monocytes/macrophages and plays important roles in the induction of CHS.

2-2OAS M2 Monocyte/Macrophage-Derived MMP12 Plays a Pivotal Role in Contact Hypersensitivity