PMID- 38340268
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240320
IS  - 1573-6822 (Electronic)
IS  - 0742-2091 (Print)
IS  - 0742-2091 (Linking)
VI  - 40
IP  - 1
DP  - 2024 Feb 10
TI  - Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental 
      asthma.
PG  - 12
LID - 10.1007/s10565-024-09852-x [doi]
LID - 12
AB  - V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), 
      a novel negative checkpoint regulator, plays an essential role in allergic 
      pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could 
      significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA 
      targeting may be a compelling approach. In this study, we examined the functional 
      mechanism of VISTA in allergic pulmonary inflammation and screened the 
      FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found 
      that VISTA deficiency primarily increased lung macrophage infiltration in the 
      OVA-induced asthma model, accompanied by an increased proportion of M1 
      macrophages (CD11b(+)F4/80(+)CD86(+)) and a decreased proportion of M2 
      macrophages (CD11b(+)F4/80(+)CD206(+)). Further in vitro studies showed that 
      VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone 
      marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil 
      (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface 
      plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 microM) as well as its 
      active form, baloxavir acid (BXA) (KD = 0.21 microM), could directly bind to VISTA 
      with high affinity. Notably, treatment with BXM significantly ameliorated asthma 
      symptoms, including less lung inflammation, mucus secretion, and the generation 
      of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by 
      anti-VISTA monoclonal antibody treatment. BXM administration also reduced the 
      pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, 
      our study indicates that VISTA regulates pulmonary inflammation in allergic 
      asthma by regulating macrophage polarization and baloxavir marboxil, and an old 
      drug might be a new treatment for allergic asthma through targeting VISTA.
CI  - (c) 2024. The Author(s).
FAU - Di, Jian-Wen
AU  - Di JW
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Wang, Yi-Xin
AU  - Wang YX
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Ma, Rui-Xue
AU  - Ma RX
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Luo, Zhi-Jie
AU  - Luo ZJ
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Chen, Wen-Ting
AU  - Chen WT
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Liu, Wan-Mei
AU  - Liu WM
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Yuan, Ding-Yi
AU  - Yuan DY
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Zhang, Yu-Ying
AU  - Zhang YY
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Wu, Yin-Hao
AU  - Wu YH
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China.
FAU - Chen, Cai-Ping
AU  - Chen CP
AD  - State Key Laboratory of Natural Medicines, China Pharmaceutical University, 
      Nanjing, 210009, China. caiping.chen@cpu.edu.cn.
AD  - Chongqing Innovation Institute of China Pharmaceutical University, Chongqing, 
      401135, China. caiping.chen@cpu.edu.cn.
FAU - Liu, Jun
AU  - Liu J
AD  - New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, 
      China. junliu@cpu.edu.cn.
LA  - eng
GR  - CSTB2022NSCQ-MSX1649/Natural Science Foundation Project of Chongqing, Chongqing 
      Science and Technology Commission/
GR  - 81973361/National Natural Science Foundation of China/
GR  - BK20202009/Natural Science Foundation of Jiangsu Province/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20240210
PL  - Switzerland
TA  - Cell Biol Toxicol
JT  - Cell biology and toxicology
JID - 8506639
RN  - 4G86Y4JT3F (baloxavir)
RN  - 0 (Dibenzothiepins)
RN  - 0 (Morpholines)
RN  - 0 (Pyridones)
RN  - 0 (Triazines)
RN  - 0 (Vsir protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Asthma/drug therapy/metabolism
MH  - *Dibenzothiepins
MH  - Morpholines/pharmacology/therapeutic use
MH  - *Pneumonia
MH  - *Pyridones
MH  - *Triazines
PMC - PMC10858940
OTO - NOTNLM
OT  - Asthma
OT  - Baloxavir marboxil
OT  - Macrophage polarization
OT  - VISTA
COIS- The authors declare no competing interests.
EDAT- 2024/02/10 14:51
MHDA- 2024/02/10 22:54
PMCR- 2024/02/10
CRDT- 2024/02/10 11:19
PHST- 2023/11/14 00:00 [received]
PHST- 2024/01/26 00:00 [accepted]
PHST- 2024/02/10 22:54 [medline]
PHST- 2024/02/10 14:51 [pubmed]
PHST- 2024/02/10 11:19 [entrez]
PHST- 2024/02/10 00:00 [pmc-release]
AID - 10.1007/s10565-024-09852-x [pii]
AID - 9852 [pii]
AID - 10.1007/s10565-024-09852-x [doi]
PST - epublish
SO  - Cell Biol Toxicol. 2024 Feb 10;40(1):12. doi: 10.1007/s10565-024-09852-x.