1 Lab. of Stem Cell Stress, International Res. Center for Med. Sci., Kumamoto Univ. 2 Lab. of Epitranscriptome in hematopoiesis, International Res. Center for Med. Sci., Kumamoto Univ.3 Div. of Skin Regeneration and Aging, Med. Inst. of Bioregulation, Kyushu Univ.4 IVIM Technol. Inc.5 Grad. Sch. of Med. Sci. and Eng., Coll. of Life Sci. and Bioeng., Korea Adv. Inst. of Sci. and Technol.6 Center for Metabolic Regulation of Healthy Aging, Kumamoto Univ.SKIN-DERIVED G-CSF DRIVES PATHOLOGICAL GRANULOPOIESIS UPON PSORIASIS33Psoriasis is an autoimmune-driven disease leading to loss of skin functional integrity through direct immune-mediated tissue destruction and loss of keratinocytes’ homeostasis. While T-cell particularly Th17 is a key immune mediator for the disease pathogenesis, blocking its function does not lead to complete recovery. Recent studies suggested that neutrophil would be a promising therapeutic target. However, further investigation remains to be done to clarify its role. We aim to elucidate the mechanistic basis of neutrophil role in psoriasis in the context of skin-bone marrow (BM) crosstalk.Our study employs a psoriasis mouse model induced by topical administration of IMQ (Imiquimod, TLR7-agonist) on dorsal skin. Firstly, using 3D-intravital imaging and flowcytometry, we observed a time-dependent transvascular skin-neutrophil accumulation upon psoriasis. Neutrophil overburden in skin drives pathogenesis, as its depletion by systemic injection of anti-Ly6G neutralizing antibody which does not deplete peripheral blood nor BM neutrophil partially mitigates the psoriasis disease. Analysis of hematopoietic progenitors in BM revealed that psoriasis activates the BM hematopoiesis to emergency granulopoiesis through expansion of the hematopoietic progenitors. To clarify what drives emergency granulopoiesis, we profiled myelopoiesis-supporting cytokines in the circulation and found that G-CSF increases by more than 10-fold upon psoriasis and is exclusively expressed in skin-resident endothelial cell. We block the skin-bone marrow crosstalk upon psoriasis by administering in vivo anti-G-CSF which lowers skin-neutrophil burden and attenuates the skin inflammation symptoms. Finally, re-analysis of publicly available RNA-seq datasets suggests neutrophil activation and G-CSF secretion by endothelial cells in human psoriatic skin.Our findings uncover the pathological role of neutrophil via skin-BM crosstalk in skin psoriasis disease, and will help to develop an effective therapy against psoriasis by targeting skin neutrophil in a combination with existing drugs.○Tomson Kosasih1 Tatsuya Morishima1,2 Kanako Wakahashi1 Sohyeon Lee4Jungyeon Yoon4 Pilhan Kim4,5 Aiko Sada3 Hitoshi Takizawa1,6P 003
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