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Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation.

Abstract：

:Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice. Peripheral blood mononuclear cells isolated from CHIKV-infected patients showed elevated NLRP3, caspase-1 and interleukin-18 messenger RNA expression and, using a mouse model of CHIKV infection, we found that high NLRP3 expression was associated with peak inflammatory symptoms. Inhibition of NLRP3 activation using the small-molecule inhibitor MCC950 resulted in reduced CHIKV-induced inflammation and abrogated osteoclastogenic bone loss and myositis, but did not affect in vivo viral replication. Mice treated with MCC950 displayed lower expression levels of the cytokines interleukin-6, chemokine ligand 2 and tumour necrosis factor in joint tissue. Interestingly, MCC950 treatment abrogated disease signs in mice infected with a related arthritogenic alphavirus, Ross River virus, but not in mice infected with West Nile virus-a flavivirus. Here, using mouse models of alphavirus-induced musculoskeletal disease, we demonstrate that NLRP3 inhibition in vivo can reduce inflammatory pathology and that further development of therapeutic solutions targeting inflammasome function could help treat arboviral diseases.

journal_name

Nat Microbiol

journal_title

Nature microbiology

authors

Chen W,Foo SS,Zaid A,Teng TS,Herrero LJ,Wolf S,Tharmarajah K,Vu LD,van Vreden C,Taylor A,Freitas JR,Li RW,Woodruff TM,Gordon R,Ojcius DM,Nakaya HI,Kanneganti TD,O'Neill LAJ,Robertson AAB,King NJ,Suhrbier A,Coope

doi

10.1038/s41564-017-0015-4

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

1435-1445

issue

10

issn

2058-5276

pii

10.1038/s41564-017-0015-4

journal_volume

2

pub_type

杂志文章

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