Abstract
Severe acute respiratory syndrome–associated coronavirus (SARS-CoV) initiates the cytokine/chemokine storm-mediated lung injury. The SARS-CoV unique domain (SUD) with three macrodomains (N, M, and C), showing the G-quadruplex binding activity, was examined the possible role in SARS pathogenesis in this study. The chemokine profile analysis indicated that SARS-CoV SUD significantly up-regulated the expression of CXCL10, CCL5 and interleukin (IL)-1β in human lung epithelial cells and in the lung tissues of the mice intratracheally instilled with the recombinant plasmids. Among the SUD subdomains, SUD-MC substantially activated AP-1-mediated CXCL10 expression in vitro. In the wild type mice, SARS-CoV SUD-MC triggered the pulmonary infiltration of macrophages and monocytes, inducing CXCL10-mediated inflammatory responses and severe diffuse alveolar damage symptoms. Moreover, SUD-MC actuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-dependent pulmonary inflammation, as confirmed by the NLRP3 inflammasome inhibitor and the NLRP3−/− mouse model. This study demonstrated that SARS-CoV SUD modulated NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, providing the potential therapeutic targets for developing the antiviral agents.
Highlights
Severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) is a highly contagious agent that causes severe lung damage, including bronchial epithelial dysfunction, pulmonary infiltration with immune cells, and even lung fibrosis [1,2,3,4]
Our results suggested that NLRP3 inflammasome pathway plays a key role in the activation of AP-1-mediated CXCL10 expression by SARS-CoV SARS-CoV unique domain (SUD)-MC, proinflammatory chemokines and cytokines of which, such as CXCL10 and IL-1β, trigger the infiltration of macrophages/monocytes in the lung tissues (Figure 10)
This study demonstrated the biological activity of SARS-CoV SUD in modulating NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, which provides the potential therapeutic targets for developing the agents against the coronavirus-induced diseases
Summary
Severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) is a highly contagious agent that causes severe lung damage, including bronchial epithelial dysfunction, pulmonary infiltration with immune cells, and even lung fibrosis [1,2,3,4]. SSUUDD--MMCC SSiiggnniiffiiccaannttllyy IInndduucceedd tthhee PPuullmmoonnaarryy IInnfifillttrraattiioonn ooff IImmmmuunnee CCeellllss aanndd CCaauusseedd LLuunngg IInnjjuurryy in iMn iMceice. The NLRP3-inflammasome inhibitor MCC950 significantly decreased SUD-MC induced c-Jun mediated activation of IL-1β and CXCL10 expression in human lung epithelial cells (Figure 8). Our results suggested that NLRP3 inflammasome pathway plays a key role in the activation of AP-1-mediated CXCL10 expression by SARS-CoV SUD-MC, proinflammatory chemokines and cytokines of which, such as CXCL10 and IL-1β, trigger the infiltration of macrophages/monocytes in the lung tissues (Figure 10). This study demonstrated the biological activity of SARS-CoV SUD in modulating NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, which provides the potential therapeutic targets for developing the agents against the coronavirus-induced diseases. 5 -AGTG CTCGAG CG TAGAATCTCTTCCTTAGC-3 5 -AGTG GGTACC T TGGAATTTGAGAGAAATG-3 5 -AGTG CTCGAG CG TGACGAAGTGAGGTATCC-3 5 -AGTG GGTACC T TCAAAGACATCTGAGGAG-3 5 -AGTG CTCGAG CG TGTGTGGAGATTAGTGTTGTC-3
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