Long noncoding RNA IRL regulates NF-κB-mediated immune responses through suppression of miR-27c-3p-dependent IRAK4 downregulation in teleost fish

Abstract

Growing pieces of evidence show that the long noncoding RNAs (lncRNAs) as new regulators participate in the regulation of various physiological and pathological processes. The study of lncRNA in lower invertebrates is still unclear compared with that in mammals. Here, we identified a novel lncRNA, termed IRAK4-related lncRNA (IRL), as a key regulator for innate immunity in teleost fish. We find that miR-27c-3p inhibits IRAK4 expression and thus weakens the NF-κB-mediated signaling pathway. Furthermore, the Gram-negative bacterium Vibrio anguillarum and lipopolysaccharide significantly upregulated host lncRNA IRL expression. Results indicate that IRL functions as a competing endogenous RNA for miR-27c-3p to regulate protein abundance of IRAK4; thus, invading microorganisms are eliminated and immune responses are promoted. Our study also demonstrates the regulation mechanism that lncRNA IRL can competitively adsorb miRNA to regulate the miR-27c-3p/IRAK4 axis that is widespread in teleost fish. Growing pieces of evidence show that the long noncoding RNAs (lncRNAs) as new regulators participate in the regulation of various physiological and pathological processes. The study of lncRNA in lower invertebrates is still unclear compared with that in mammals. Here, we identified a novel lncRNA, termed IRAK4-related lncRNA (IRL), as a key regulator for innate immunity in teleost fish. We find that miR-27c-3p inhibits IRAK4 expression and thus weakens the NF-κB-mediated signaling pathway. Furthermore, the Gram-negative bacterium Vibrio anguillarum and lipopolysaccharide significantly upregulated host lncRNA IRL expression. Results indicate that IRL functions as a competing endogenous RNA for miR-27c-3p to regulate protein abundance of IRAK4; thus, invading microorganisms are eliminated and immune responses are promoted. Our study also demonstrates the regulation mechanism that lncRNA IRL can competitively adsorb miRNA to regulate the miR-27c-3p/IRAK4 axis that is widespread in teleost fish. Innate immunity is the host's first line of defense against the invasion of pathogenic microorganisms. The pattern recognition receptors (PRRs), as crucial receptor molecule in the innate immune signal transmission, play crucial roles in protecting the host from pathogen invasion. Toll-like receptors (TLRs), RIG-like receptors, and nucleotide oligomerization domain-like receptors are the most important types of PRRs, and they play an irreplaceable role in helping the host identify and monitor various invasive microorganisms (1Kim T.W. Staschke K. Bulek K. Yao J. Peters K. Oh K.H. Vandenburg Y. Xiao H. Qian W. 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Moreover, nearly all TLRs (except TLR3) can activate transcription factors NF-κB and IRF3 in downstream signaling pathways through the interaction of myeloid differentiation factor 88 (MyD88) with IL-1 receptor-associated kinases (IRAKs) (5Xiong Y. Medvedev A.E. Induction of endotoxin tolerance in vivo inhibits activation of IRAK4 and increases negative regulators IRAK-M, SHIP-1, and A20.J. Leukoc. Biol. 2011; 90: 1141-1148Crossref PubMed Scopus (78) Google Scholar, 6Pattabiraman G. Murphy M. Agliano F. Karlinsey K. Medvedev A.E. IRAK4 activity controls immune responses to intracellular bacteria Listeria monocytogenes and Mycobacterium smegmatis.J. Leukoc. Biol. 2018; 104: 811-820Crossref PubMed Scopus (6) Google Scholar). Ultimately, these transcription factors activate the host’s antibacterial and inflammatory responses. IRAK4, as a member of IRAKs, is a crucial serine/threonine kinase involved in the TLR/IL-1R stimulation transduction pathway (7Li X. 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Recent studies have shown that IRAK4 is associated with some autoimmune diseases. Umar et al. (13Umar S. Palasiewicz K. Van Raemdonck K. Volin M.V. Romay B. Amin M.A. Zomorrodi R.K. Arami S. Gonzalez M. Rao V. IRAK4 inhibition: A promising strategy for treating RA joint inflammation and bone erosion.Cell. Mol. Immunol. 2020; https://doi.org/10.1038/s41423-020-0433-8Crossref Scopus (6) Google Scholar) found that IRAK4 inhibitor therapy attenuated rheumatoid arthritis disease activity by blocking TLR7-induced M1-MΦ or fibroblasts activation, as well as monokine-modulated Th1/Th17 cell polarization. Recent studies have also found that suppressed IRAK4 can inhibit plasmacytoid dendritic cells and natural killer cells from producing cytokines to treat systemic lupus erythematosus, which is an autoimmune disease that activates the circulating immune complexes and type I interferon and then produces proinflammatory cytokines and chemokines; this phenomenon to autoimmune reactions and organ inflammations (14Hjorton K. Hagberg N. Israelsson E. Jinton L. Berggren O. Sandling J.K. Thörn K. Mo J. Eloranta M.-L. Rönnblom L. Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor.Arthritis Res. Ther. 2018; 20: 1-11Crossref PubMed Scopus (23) Google Scholar). Studies show that IRAK4-deficient children are susceptible to life-threatening pyogenic infections; therefore, IRAK4 is essential for the innate immune system (7Li X. IRAK4 in TLR/IL-1R signaling: Possible clinical applications.Eur. J. 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However, evidence shown that can play a critical regulator involved in and RNA in 2008; PubMed Scopus Google Scholar). Recent studies also show that regulate with or some as competing endogenous RNAs and with by competing for regulation by long noncoding Rev. PubMed Scopus Google Scholar, P.J. noncoding in and Full Text Full Text PDF PubMed Scopus Google Scholar, M. of PubMed Scopus Google Scholar). have in as and to that an of have in the of the are widespread in all is of for are a of with a of to S. of miRNA 2010; PubMed Scopus Google Scholar). The study of miRNA in shown that miRNA an irreplaceable important role in from lower to mammals. Studies have shown that miRNA can participate in various physiological and pathological as cell and differentiation S. H. K. K. H. cell is by the 2005; PubMed Scopus Google Scholar). expression through to the of the by or studies show that have as the this are miRNA lncRNA can as a to competitively bind miRNA to regulate M. X. H. L. Z. H. L. J. of long to lncRNA in PubMed Scopus Google Scholar). mechanism first in by et M. D. J. a new mechanism for regulation of 2007; PubMed Scopus Google Scholar). found that lncRNA can regulate the expression of by competitively evidence shown that the mechanism of in and L. L. J. B. A of and 2010; 465: PubMed Scopus Google Scholar). However, the mechanism to found in and and is the mechanism in lower as fish. this we first identified a involved in NF-κB signaling in teleost fish. Our that the miR-27c-3p can regulate IRAK4 expression and the immune We that a lncRNA, can as a for miR-27c-3p to IRAK4 as a immune responses are Our to the of the mechanism in teleost also a for the of lncRNA in the innate immune in lower from in for The bacterial as Y. J. T. the NF-κB pathway in teleost by Immunol. PubMed Scopus Google Scholar). with of Vibrio anguillarum or of lipopolysaccharide of physiological to the and the for RNA in with the of for the and of and the by the of M. cells and M. cells in with and cells in with and in stimulation with an of and for RNA L. T. inhibits immune responses in lower through Immunol. 2020; PubMed Scopus Google Scholar). IRL and IRAK4 the of IRL and IRAK4 in M. and into The with in the with the of IRL into the which the of IRL and IRAK4 expression by the IRL and IRAK4 of M. N. and L. into the the into the I and of and then the IRL and into The with in the with An miR-27c-3p by miR-27c-3p into the The of the by and through the and to the The miR-27c-3p are RNAs with The miR-27c-3p and The negative RNA and miRNA are RNAs that intracellular and activity in the RNA pathway. The miR-27c-3p inhibitor The negative inhibitor The RNA for IRL are as the the the negative RNA and The RNA for IRAK4 is as the and The RNA and RNA and RNA from the RNA to the RNA and by RNA which of RNA to eliminate The and the RNA to the expression by The RNA by miRNA and miRNA to transcription of The expression of miR-27c-3p by the miRNA in an and as negative controls to lncRNA, and miRNA T. W. L. noncoding RNA responses through in lower 2020; PubMed Scopus Google Scholar). are in The IRL or and the of the with miR-27c-3p into the system the regulation of IRL or IRAK4, with IRAK4 expression or IRL expression with and T. W. L. noncoding RNA responses through in lower 2020; PubMed Scopus Google miR-27c-3p or negative the cells for activity the system The miR-27c-3p with miR-27c-3p or IRL expression into the cells for the activity against the The of in in of to for and and in The protein in the cell with the protein detection then to and to by The is with with The against IRAK4 and and or The of The by The with a IRL and with in The with the RNA and RNA with and with an The from with for The complexes by RNA from the and to the expression of The of as T. J. innate immune in Immunol. 2018; PubMed Scopus Google Scholar). IRL is involved in the regulation with or miR-27c-3p for RNA that IRL the to bind to with or for and with and the RNA from the and the expression of miRNA by in with to the the cell with cell the the in The an and with The of and cells to the W. Wu Y. X. the of to of Immunol. 2018; PubMed Scopus Google Scholar). are as the from to the The expression the and by of by of expression and the 2001; PubMed Scopus Google Scholar). 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K. L. J. Wu X. X. B. Z. J. and to activate NF-κB pathway and and of 2020; PubMed Scopus Google Scholar). these that IRL as a in inflammatory responses and cell and cell The in cell and cell are a of the regulation of IRL innate immune responses. IRL can regulate the antibacterial responses and the expression of inflammatory the bacterial of cells and cell and cell have to as by competitively L. T. inhibits immune responses in lower through Immunol. 2020; PubMed Scopus Google Scholar, T. J. innate immune in Immunol. 2018; PubMed Scopus Google Scholar). 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The from that of miR-27c-3p suppressed the expression of IRAK4 We miR-27c-3p and into The from that of miR-27c-3p suppressed the expression of IRAK4, miR-27c-3p the expression of IRAK4 We find through detection that miR-27c-3p suppressed the expression of IRAK4 miR-27c-3p the expression of IRAK4 We that IRAK4 by We the into the and the type of IRAK4 bind to IRAK4, then miR-27c-3p can by the of from the that the miR-27c-3p of IRAK4 is significantly that of IRAK4 and these that miR-27c-3p can bind to IRAK4 and regulate the expression of that IRL with miR-27c-3p and miR-27c-3p and we IRL can regulate The from the and that IRAK4 protein expression is significantly IRL in the IRAK4 expression is significantly through of IRL the with miR-27c-3p and and the that IRL can the of miR-27c-3p IRAK4 protein expression that miR-27c-3p can inhibit IRL can the of miR-27c-3p IRAK4 The IRAK4 with IRL and various into The that IRL can the negative of miR-27c-3p the of and Moreover, we to the of the cell The that of IRL can the negative of miR-27c-3p cell stimulation We and into to the that IRL IRAK4 by the that can the negative of IRAK4 these that IRL as a for miR-27c-3p to regulate IRAK4 expression. We first the of from to the of miR-27c-3p as shown in from to fish. The in IRAK4 also from to by the IRL of L. and N. into the of as a to the evidence that miR-27c-3p IRL is that miR-27c-3p are to with the types of L. and N. they the activity of cells with types indicate that miR-27c-3p can the IRAK4 in that miR-27c-3p is and its is also to some We also the that the interaction lncRNA IRL and miR-27c-3p also in this we first the of IRL is that the of IRL is IRL in these as in the of miR-27c-3p we of L. and N. IRL and with to IRL in also with that miR-27c-3p can the activity of the of IRL in the Furthermore, to L. and N. IRL can miR-27c-3p we and found that L. and N. IRL the of miR-27c-3p the miR-27c-3p indicate that IRL as endogenous RNA to with miR-27c-3p that IRL and this is important for are one of the most to the the various Gram-negative bacteria have identified as that in in V. V. as a pathogen that can and is to and is the of Vibrio infections in various V. anguillarum by the and the of the disease and and thus to the in and the S. T. J. W. F. of transcription in PubMed Scopus Google Scholar). teleost the innate immune a and central defense bacterial to teleost and a of signaling in to invading bacteria S. T. J. W. F. of transcription in PubMed Scopus Google Scholar). we an interaction that teleost antibacterial signaling miR-27c-3p can the expression of IRAK4 and inflammatory and this the bacteria to the host Furthermore, we that lncRNA IRL as an endogenous RNA to with miR-27c-3p and the inflammatory responses. we find that V. anguillarum or stimulation IRL expression in IRL can an of miR-27c-3p thus the of antibacterial immune and appropriate inflammatory responses are The the critical roles of in inflammatory responses by bacterial and that regulation mechanism in teleost fish. the most is TLRs, and this receptor is in various pathogenic and TLRs, NLRs and A of pathogen that in innate Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar). the in are most TLRs (except TLR3) can activate the NF-κB signaling pathway by MyD88 and induce the of inflammatory cytokines and in the innate antibacterial IRAK4 identified as a critical central molecule in the NF-κB signaling pathway, and the mechanism of signal transduction in the S. S. T. N. Rao P. The mechanism of activation of and IRAK4 by interleukin-1 and Toll-like receptor J. PubMed Scopus Google Scholar). an of studies have shown that can regulate the immune by et al. X. Li X. Y. K. Y. Li Y. Y. Wu M. host defense to bacteria by inflammatory responses to 1-14Crossref Scopus Google Scholar) that the inflammatory by to the and the defense of the host against Gram-negative bacterium in et al. Y. H. X. L. L. X. inhibits inflammatory production in by PubMed Scopus Google Scholar) also that inhibits inflammatory production in by IRAK4 in that can regulate the immune by IRAK4 have in lower studies have shown that and inhibit the inflammatory Gram-negative bacteria or by IRAK4 in T. J. X. The in the inflammatory responses to Gram-negative bacteria by IL-1 receptor-associated kinase Biol. Chem. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, X. L. T. The the inflammatory in teleost Immunol. PubMed Scopus Google Scholar). The study that novel miR-27c-3p and play critical roles in host inflammatory responses stimulation in that miR-27c-3p a negative IRL a role in the pathway. However, we found that the some proinflammatory We that for the one is that IRL is also to or the expression of these proinflammatory cytokines by the expression of thus the regulation of these cytokines by this which is the we that this is by the of the the the mechanism of is and and in the in lower in the teleost is also complex miRNA regulation in teleost in innate the and have to the inflammatory responses to Gram-negative bacteria by IRAK4 T. J. X. The in the inflammatory responses to Gram-negative bacteria by IL-1 receptor-associated kinase Biol. Chem. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, X. L. T. The the inflammatory in teleost Immunol. PubMed Scopus Google Scholar). and have to NF-κB-mediated inflammatory MyD88 in Y. J. T. the NF-κB pathway in teleost by Immunol. PubMed Scopus Google Scholar, Y. J. T. to the of NF-κB-mediated inflammatory in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, studies that miRNA can with lncRNA to form a for the immune can regulate expression and lncRNA can as a for to the of this the of interaction in lower T. W. L. noncoding RNA responses through in lower 2020; PubMed Scopus Google Scholar). this miR-27c-3p is to a novel miRNA IRAK4 in miR-27c-3p IRAK4 expression and antibacterial responses. The negative mechanism a strategy of Gram-negative bacteria for by the host antibacterial immune pieces of evidence that some can play as a to regulate the expression of in by competitively the mechanism first in and in and most with this are in the M. Z. X. Y. H. L. J. and of identified novel lncRNA for of PubMed Scopus Google Scholar, M. Z. M. J. J. of of and with associated and in PubMed Scopus Google Scholar). lncRNA in the of and that of a of F. Y. Y. X. P. X. in by the Res. 2020; PubMed Scopus Google Scholar). Moreover, the lncRNA to as a for by to regulate expression and the pathway J. Z. H. as inhibits by to regulate expression and the 2018; 17: PubMed Scopus Google Scholar). lncRNA is significantly in and to the pathological by expression in is a downstream of in the of B. Yao J. Li Li by as a competing endogenous Res. PubMed Scopus Google Scholar). a of have found in lower the and of in lower are still in mammals. Our study that lncRNA IRL can as a to regulate antibacterial pathway through competitively miR-27c-3p in teleost fish. study is the first one to that lncRNA can regulate antibacterial pathways by TLRs through the mechanism in lower which for and the of immune we find that miR-27c-3p a negative IRL a role in the regulation of inflammatory responses. Furthermore, we identified that IRL as a regulator of inflammatory responses as a for miR-27c-3p to its IRAK4 thus, immune and immune are Our the critical roles of in inflammatory which for the and the of immune are the and the The that they have of with the of this and the T. X. the W. and T. X. the W. and T. X. W. and T. X. the W. and T. X. study by of and and

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