Targeting inflammatory polarization of macrophages and cell surface calreticulin in hemophagocytic lymphohistiocytosis

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15199
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Hayashi Yoshihiro 東京薬科大学, 生命科学部, 講師 (30802590)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 血球貪食症候群 / マクロファージ

Outline of Final Research Achievements

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder of severe hyper-inflammation caused by uncontrolled proliferation of activated immune cells. We expected to reveal essential common axis for HLH development, and provide the clue for the targeted treatments for a significant population of HLH patients.
By focusing on type I polarization of macrophages, we confirmed that calreticulin in a cell surface form is induced on macrophages during type I inflammatory polarization. Pharmacological and genetic inhibition of Hif1a and Nos2 signaling, critical factors for type I polarization, did not block type I polarization of macrophages in HLH mice, suggesting the existence of other critical factor for type I polarization. As calreticulin functions as a perforin inhibitor, future study will be needed to investigate whether calreticulin-perforin axis could play a central role at synapse between phagocytes-effectors and HLH pathogenesis.

Free Research Field

血液学

Academic Significance and Societal Importance of the Research Achievements

血球貪食症候群（HLH）の病態形成において炎症性マクロファージが中心的な役割を果たす。このマクロファージを標的とした治療は、HLHの新規治療戦略構築へとつながる。本研究において、種々の細胞および遺伝子改変マウスを用いた検討により、炎症性局在変化に伴って、マクロファージ表面にパーフォリン阻害作用を持つカルレティキュリンが誘導されることが明らかとなった。マクロファージの極性変化やカルレティキュリンの阻害による病態への影響については、今後の研究において明らかにしていく必要がある。