A novel complement inhibitor sMAP-FH targeting both the lectin and alternative complement pathways.
Animals
Complement Activation
/ immunology
Complement Factor H
/ immunology
Complement Inactivating Agents
/ immunology
Complement Pathway, Alternative
/ immunology
Female
Humans
Lectins
/ immunology
Mannose-Binding Lectin
/ immunology
Mannose-Binding Protein-Associated Serine Proteases
/ immunology
Mice
Mice, Inbred C57BL
MAp44
alternative complement pathway
factor H
lectin complement pathway
small mannose-binding lectin-associated protein
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
30
09
2019
revised:
24
12
2019
accepted:
08
03
2020
pubmed:
29
3
2020
medline:
23
1
2021
entrez:
29
3
2020
Statut:
ppublish
Résumé
Inhibition of the complement activation has emerged as an option for treatment of a range of diseases. Activation of the lectin and alternative pathways (LP and AP, respectively) contribute to the deterioration of conditions in certain diseases such as ischemia-reperfusion injuries and age-related macular degeneration (AMD). In the current study, we generated dual complement inhibitors of the pathways MAp44-FH and sMAP-FH by fusing full-length MAp44 or small mannose-binding lectin-associated protein (sMAP), LP regulators, with the N-terminal five short consensus repeat (SCR) domains of complement factor H (SCR1/5-FH), an AP regulator. The murine forms of both fusion proteins formed a complex with endogenous mannose-binding lectin (MBL) or ficolin A in the circulation when administered in mice intraperitoneally. Multiple complement activation assays revealed that sMAP-FH had significantly higher inhibitory effects on activation of the LP and AP in vivo as well as in vitro compared to MAp44-FH. Human form of sMAP-FH also showed dual inhibitory effects on LP and AP activation in human sera. Our results indicate that the novel fusion protein sMAP-FH inhibits both the LP and AP activation in mice and in human sera, and could be an effective therapeutic agent for diseases in which both the LP and AP activation are significantly involved.
Identifiants
pubmed: 32219899
doi: 10.1096/fj.201902475R
doi:
Substances chimiques
CFH protein, human
0
Complement Inactivating Agents
0
Lectins
0
Mannose-Binding Lectin
0
Mbl2 protein, mouse
0
Complement Factor H
80295-65-4
Mannose-Binding Protein-Associated Serine Proteases
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6598-6612Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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