Antibody-mediated inhibition of integrin α5β1 blocks neurotoxic prion peptide PrP106-126-induced activation of BV2 microglia.
Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The identification of cell surface molecules that mediate the prion protein (PrP) synthetic peptide interaction with microglia is of great significance as it represents potential target molecules to modulate the events leading to the pathophysiology of prion diseases. Here, we carried out in vitro experiments to investigate the involvement of α5β1 integrin in neurotoxic prion peptide PrP(106-126)-induced activation of BV2 microglia. The results showed that the exposure to PrP(106-126) upregulated the mRNA expression of proinflammatory factors (IL-1 β, IL-6, and iNOS) and NALP3 inflammasome components (NALP3 and ASC), increased the release of iNOS and its product nitric oxide, and stimulated NF-κB activation. Blockade of α5β1 integrin with monoclonal antibody BMC5 prior to PrP(106-126) treatment abrogated the upregulation of the mRNA expression of IL-1 β, IL-6, iNOS, and ASC, but had no effect on the mRNA expression of NALP3, blocked the release of iNOS and nitric oxide, and inhibited NF-κB activation. These results suggest that α5β1 integrin is involved in the PrP(106-126)-induced microglial activation through the participation in the activation of NF-κB and NALP3/ASC inflammasome. Our study unveils a previously unidentified role of α5β1 integrin as an intermediate signaling molecule in neurotoxic prion peptides-microglia interactions and identifies a potential molecular target for the modulation of prion-induced microglial activation.
The State Key Laboratories for Agrobiotechnology, Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
Jiaxin
J
Chang
Lifeng
L
Yang
Mohammed
M
Kouadir
Yun
Y
Peng
Siming
S
Zhang
Fushan
F
Shi
Xiangmei
X
Zhou
Xiaomin
X
Yin
Deming
D
Zhao
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D017096:Prion Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011328:Prions / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D039081:Integrin alpha5beta1; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010446:Peptide Fragments; D011328:Prions; C498534:Pycard protein, mouse; D012333:RNA, Messenger; C082632:prion protein (106-126); D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse