Abstract
The inflammasome has an essential function in innate immune, responding to a wide variety of stimuli. Here we show that the lncRNA Neat1 promotes the activation of several inflammasomes. Neat1 associates with the NLRP3, NLRC4, and AIM2 inflammasomes in mouse macrophages to enhance their assembly and subsequent pro-caspase-1 processing. Neat1 also stabilizes the mature caspase-1 to promote interleukin-1β production and pyroptosis. Upon stimulation with inflammasome-activating signals, Neat1, which normally resides in the paraspeckles, disassociates from these nuclear bodies and translocates to the cytoplasm to modulate inflammasome activation using above mechanism. Neat1 is also up-regulated under hypoxic conditions in a HIF-2α-dependent manner, mediating the effect of hypoxia on inflammasomes. Moreover, in the mouse models of peritonitis and pneumonia, Neat1 deficiency significantly reduces inflammatory responses. These results reveal a previously unrecognized role of lncRNAs in innate immunity, and suggest that Neat1 is a common mediator for inflammasome stimuli.
Highlights
The inflammasome has an essential function in innate immune, responding to a wide variety of stimuli
To investigate whether long non-coding RNAs (lncRNAs) may regulate inflammasomes, we set out to identify lncRNAs that are associated with the NLRP3 inflammasome in murine immortalized bone marrow-derived macrophages
Several noncoding RNAs were found to be enriched in NLRP3 inflammasomes, including those encoded by Ankrd[52], Hipk[3], Pou2f2, Neat[1], Gm26917, Gm42418, Snord[34], Junos, Gm26767, and Gm23935 (Supplementary Fig. 1a)
Summary
The inflammasome has an essential function in innate immune, responding to a wide variety of stimuli. In the mouse models of peritonitis and pneumonia, Neat[1] deficiency significantly reduces inflammatory responses These results reveal a previously unrecognized role of lncRNAs in innate immunity, and suggest that Neat[1] is a common mediator for inflammasome stimuli. 1234567890():,; Inflammasomes are a group of multicomponent signaling platforms in the cytoplasm that control inflammatory response and anti-pathogen defense against a wide range of infection and damage signals[1,2,3,4] These signals, including pathogen-associated molecular patterns (PAMPs) and damageassociated molecular patterns (DAMPs)[2,5], directly or indirectly activate one or more innate pattern recognition receptors (PRRs), which include nucleotide-binding domain (NBD) and leucinerich repeat (LRR)-containing receptors (NLRs, e.g., NLRP1, NLRP3, and NLRC4), cytosolic DNA sensors (AIM2), and Pyrin ( known as TRIM20)[6,7,8]. A salient unresolved issue is how various inflammasomes collectively are able to respond to such a wide spectrum of stimuli
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