SGK1 negatively regulates inflammatory immune responses and protects against alveolar bone loss through modulation of TRAF3 activity

Abstract

Serum- and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that plays important roles in the cellular stress response. While SGK1 has been reported to restrain inflammatory immune responses, the molecular mechanisms involved remain elusive, especially in oral bacteria-induced inflammatory milieu. Here, we found that SGK1 curtails Porphyromonas gingivalis–induced inflammatory responses through maintaining levels of tumor necrosis factor receptor-associated factor (TRAF) 3, thereby suppressing NF-κB signaling. Specifically, SGK1 inhibition significantly enhances production of proinflammatory cytokines, including tumor necrosis factor α, interleukin (IL)-6, IL-1β, and IL-8 in P. gingivalis–stimulated innate immune cells. The results were confirmed with siRNA and LysM-Cre–mediated SGK1 KO mice. Moreover, SGK1 deletion robustly increased NF-κB activity and c-Jun expression but failed to alter the activation of mitogen-activated protein kinase signaling pathways. Further mechanistic data revealed that SGK1 deletion elevates TRAF2 phosphorylation, leading to TRAF3 degradation in a proteasome-dependent manner. Importantly, siRNA-mediated traf3 silencing or c-Jun overexpression mimics the effect of SGK1 inhibition on P. gingivalis–induced inflammatory cytokines and NF-κB activation. In addition, using a P. gingivalis infection–induced periodontal bone loss model, we found that SGK1 inhibition modulates TRAF3 and c-Jun expression, aggravates inflammatory responses in gingival tissues, and exacerbates alveolar bone loss. Altogether, we demonstrated for the first time that SGK1 acts as a rheostat to limit P. gingivalis–induced inflammatory immune responses and mapped out a novel SGK1–TRAF2/3–c-Jun–NF-κB signaling axis. These findings provide novel insights into the anti-inflammatory molecular mechanisms of SGK1 and suggest novel interventional targets to inflammatory diseases relevant beyond the oral cavity. Serum- and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that plays important roles in the cellular stress response. While SGK1 has been reported to restrain inflammatory immune responses, the molecular mechanisms involved remain elusive, especially in oral bacteria-induced inflammatory milieu. Here, we found that SGK1 curtails Porphyromonas gingivalis–induced inflammatory responses through maintaining levels of tumor necrosis factor receptor-associated factor (TRAF) 3, thereby suppressing NF-κB signaling. Specifically, SGK1 inhibition significantly enhances production of proinflammatory cytokines, including tumor necrosis factor α, interleukin (IL)-6, IL-1β, and IL-8 in P. gingivalis–stimulated innate immune cells. The results were confirmed with siRNA and LysM-Cre–mediated SGK1 KO mice. Moreover, SGK1 deletion robustly increased NF-κB activity and c-Jun expression but failed to alter the activation of mitogen-activated protein kinase signaling pathways. Further mechanistic data revealed that SGK1 deletion elevates TRAF2 phosphorylation, leading to TRAF3 degradation in a proteasome-dependent manner. Importantly, siRNA-mediated traf3 silencing or c-Jun overexpression mimics the effect of SGK1 inhibition on P. gingivalis–induced inflammatory cytokines and NF-κB activation. In addition, using a P. gingivalis infection–induced periodontal bone loss model, we found that SGK1 inhibition modulates TRAF3 and c-Jun expression, aggravates inflammatory responses in gingival tissues, and exacerbates alveolar bone loss. Altogether, we demonstrated for the first time that SGK1 acts as a rheostat to limit P. gingivalis–induced inflammatory immune responses and mapped out a novel SGK1–TRAF2/3–c-Jun–NF-κB signaling axis. These findings provide novel insights into the anti-inflammatory molecular mechanisms of SGK1 and suggest novel interventional targets to inflammatory diseases relevant beyond the oral cavity. Homeostasis between proinflammatory and anti-inflammatory response is critical to the outcome of immune responses and progression of many inflammatory diseases. Concomitant to initiation of proinflammatory responses, anti-inflammatory mechanisms are also ignited to restrain the overwhelming inflammation (1Murray P.J. Smale S.T. Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways.Nat. Immunol. 2012; 13: 916-924Crossref PubMed Scopus (123) Google Scholar, 2Fullerton J.N. Gilroy D.W. Resolution of inflammation: a new therapeutic frontier.Nat. Rev. Drug Discov. 2016; 15: 551-567Crossref PubMed Scopus (443) Google Scholar). In this regard, our and other studies have demonstrated that activation of a variety of signaling molecules, such as PI3K, PKB/Akt, mammalian target of rapamycin complex (mTORC) 1, tumor necrosis factor α–induced protein 3 (TNFAIP3/A20), glycogen synthase kinase 3 beta (GSK3β), Janus kinase 3, and wingless-related integration site 3a, restrains the magnitude and intensity of inflammation (3Adamowicz K. Wang H. Jotwani R. Zeller I. Potempa J. Scott D.A. Inhibition of GSK3 abolishes bacterial-induced periodontal bone loss in mice.Mol. Med. 2012; 18: 1190-1196Crossref PubMed Scopus (26) Google Scholar, 4Li Y. Mooney E.C. Holden S.E. Xia X.J. Cohen D.J. Walsh S.W. et al.A20 orchestrates inflammatory response in the oral mucosa through restraining NF-kappaB activity.J. Immunol. 2019; 202: 2044-2056Crossref PubMed Scopus (14) Google Scholar, 5Lu L. Yakoumatos L. Ren J. Duan H. et restrains inflammatory responses and periodontal through J. PubMed Scopus Google Scholar, Duan Ren J. Yakoumatos L. et restrains the intensity of inflammation and through Immunol. PubMed Scopus Google Scholar, K. of the signaling by Porphyromonas gingivalis and PubMed Scopus Google Scholar). in the of anti-inflammatory is that anti-inflammatory response is with proinflammatory to and acts as a a negative (1Murray P.J. Smale S.T. Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways.Nat. Immunol. 2012; 13: 916-924Crossref PubMed Scopus (123) Google Scholar, 2Fullerton J.N. Gilroy D.W. Resolution of inflammation: a new therapeutic frontier.Nat. Rev. Drug Discov. 2016; 15: 551-567Crossref PubMed Scopus (443) Google Scholar). is a inflammatory by gingival inflammation and of alveolar bone and the is that of the in the has L. of in in the and 2012; PubMed Scopus Google Scholar). In oral the of proinflammatory and anti-inflammatory responses a of immune is critical for the of gingival is a of intensity of immune inflammatory responses to reported that the increased proinflammatory cytokines, including and Porphyromonas and oral 2012; PubMed Scopus Google Scholar, of innate immune signaling Porphyromonas gingivalis inflammation and 13: PubMed Scopus Google Scholar, and through of innate Med. 2012; PubMed Scopus Google and anti-inflammatory cytokines, including and are relevant to the periodontal H. proinflammatory modulates response to Porphyromonas PubMed Scopus Google Scholar). Porphyromonas gingivalis is as a and in the oral of the inflammatory immune response to the periodontal of and Immunol. PubMed Scopus Google Scholar, immune to Rev. Immunol. 15: PubMed Scopus Google Scholar, of the response by Porphyromonas J. Immunol. PubMed Scopus Google Scholar). periodontal P. gingivalis also reported to the of such as and oral P.J. and J. PubMed Scopus Google Scholar, K. of the between periodontal and PubMed Scopus Google the of regulatory mechanisms of P. While P. gingivalis found to proinflammatory responses through to on immune the P. anti-inflammatory immune mechanisms and in the periodontal remain P. gingivalis especially the activity of protein such as or and by the and magnitude of inflammatory responses K. of the signaling by Porphyromonas gingivalis and PubMed Scopus Google Scholar, P. J. et degradation of mammalian target of rapamycin by the periodontal Porphyromonas gingivalis PubMed Scopus Google Scholar, Y. Wang H. Potempa J. Scott D.A. et activation of by Porphyromonas PubMed Scopus Google Scholar). Serum- and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that to in of studies found that SGK1 to many other such as and in and PubMed Scopus Google Scholar, SGK1 in 13: PubMed Scopus Google Scholar, J. H. R. Wang H. Serum- and kinase 1 and restrains inflammation through and Immunol. PubMed Scopus Google Scholar, Y. et of by kinase PubMed Scopus Google Scholar, J. J. R. H. H. et is for and the Med. 2019; PubMed Scopus Google Scholar). of SGK1 is through with by kinase 1 the kinase and the and thereby in of innate and immune responses Y. et of by kinase PubMed Scopus Google Scholar, complex and activation of and protein kinase 1 J. PubMed Scopus Google Scholar, the of PubMed Scopus Google Scholar, H. Duan Scott D.A. et of and kinase 1 enhances inflammation and J. PubMed Scopus Google Scholar, et kinase SGK1 and of the Immunol. 15: PubMed Scopus Google Scholar). and other studies have demonstrated that SGK1 inflammatory responses and acts as a in J. H. R. Wang H. Serum- and kinase 1 and restrains inflammation through and Immunol. PubMed Scopus Google Scholar, H. Duan Scott D.A. et of and kinase 1 enhances inflammation and J. PubMed Scopus Google Scholar, J. Y. Wang Y. 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Y. et is by a in PubMed Scopus Google Scholar, of NF-kappaB activation through the complex PubMed Scopus Google Scholar). the other our and other studies found that protein and such as SGK1 and Janus kinase 3 the activity of and thereby the activity of inflammatory signaling L. Yakoumatos L. Ren J. Duan H. et restrains inflammatory responses and periodontal through J. PubMed Scopus Google Scholar, R. I. et on inflammatory PubMed Scopus (26) Google Scholar, P.J. et of by J. PubMed Scopus Google Scholar). Moreover, P. gingivalis with activation of SGK1 and such as and regulatory factor L. Yakoumatos L. Ren J. Duan H. et restrains inflammatory responses and periodontal through J. PubMed Scopus Google Scholar, Jotwani R. K. et gingivalis and signaling to inflammation and 15: PubMed Scopus Google Scholar). are studies the activation of in P. gingivalis–induced inflammatory responses SGK1 activity of and thereby in the of In this we demonstrated for the first time that SGK1 acts as a to restrain the inflammatory immune response in and a P. gingivalis–induced periodontal bone loss Moreover, our mechanistic data that SGK1 inhibition enhances expression of c-Jun and of in elevates the degradation of effect on and aggravates P. inflammatory immune In addition, SGK1 inhibition aggravates P. gingivalis–induced periodontal inflammation in and exacerbates alveolar bone that the anti-inflammatory signaling for the of novel interventional to and other inflammatory diseases beyond the oral cavity. studies have demonstrated that SGK1 to and restrains of inflammatory cytokines J. H. R. Wang H. Serum- and kinase 1 and restrains inflammation through and Immunol. PubMed Scopus Google Scholar, H. Duan Scott D.A. et of and kinase 1 enhances inflammation and J. PubMed Scopus Google Scholar, J. Y. Wang Y. J. et kinase 1 to inflammation and 2012; PubMed Scopus Google Scholar). P. gingivalis is a that and with inflammatory such as and and mechanisms periodontal and inflammatory Rev. Immunol. PubMed Scopus Google Scholar, I. Porphyromonas gingivalis in and 2016; PubMed Scopus Google Scholar, I. of activity by Porphyromonas gingivalis in and 2016; PubMed Scopus Google Scholar). SGK1 also in P. gingivalis–induced inflammation and the molecular mechanisms we first activation of SGK1 in response to the of P. gingivalis in innate cells. found that P. gingivalis of SGK1 in 1, and bone 1, and and oral 1, and the time to In other oral including and failed to 1, and P. gingivalis we of 1 a of SGK1 R. et of to as for SGK1 and J. PubMed Scopus Google Scholar, et and kinase 1 NF-kappaB signaling in PubMed Scopus Google Scholar). the of of P. gingivalis of in we Moreover, the expression of SGK1 and in or for the effect of SGK1 inhibition on the of SGK1 and results demonstrated that with P. gingivalis SGK1 in innate cells. 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Y. et is by a in PubMed Scopus Google Scholar, et for receptor-associated factor in signaling that to PubMed Scopus Google TRAF2 and TRAF3 involved in of P. gingivalis–induced In addition, we found that SGK1 to the of kinase and activation of NF-κB in response to the of P. gingivalis and TRAF3 targets for degradation by the SGK1 reported to such as and in other of and in J. PubMed Scopus Google Scholar, SGK1 of 13: PubMed Scopus Google is that SGK1 of TRAF2 and of protein and TRAF3 signaling for for Rev. PubMed Scopus Google Scholar, H. et necrosis factor receptor-associated factor (TRAF) 1 NF-kappaB PubMed Scopus Google Scholar, Wang Y. D.J. J. et NF-kappaB activation of a regulatory complex of the TRAF2 and TRAF3 and the kinase Immunol. PubMed Scopus Google Scholar). we in in that other to mechanisms in this on the of TRAF3 suppressing NF-κB our findings suggest that SGK1 TRAF3 degradation and in restrains NF-κB activity in P. gingivalis–stimulated innate immune cells. 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S.E. of activation site in the of novel by a PubMed Scopus Google Scholar). we have found that SGK1 inhibition or modulates expression of inflammatory we SGK1 P. inflammatory cytokines through of we found that silencing of TRAF3 significantly production of IL-1β, and in P. gingivalis–stimulated mimics the effect of SGK1 and Moreover, overexpression of c-Jun in a effect on the production of proinflammatory cytokines and expression of c-Jun by siRNA-mediated silencing of and and SGK1 inhibition of and of c-Jun through in response to the of P. These results suggest that SGK1 P. gingivalis–induced inflammatory production through a of TRAF3 and c-Jun P. gingivalis–induced of inflammatory responses has been demonstrated as a factor in the initiation and progression of L. Yakoumatos L. Ren J. Duan H. et restrains inflammatory responses and periodontal through J. PubMed Scopus Google Scholar, and mechanisms periodontal and inflammatory Rev. Immunol. PubMed Scopus Google Scholar, Wang H. of Porphyromonas gingivalis and in PubMed Scopus Google Scholar). we found that SGK1 inhibition and expression in P. gingivalis–stimulated immune we SGK1 inhibition exacerbates the of periodontal bone loss using a of P. gingivalis–induced (3Adamowicz K. Wang H. Jotwani R. Zeller I. Potempa J. Scott D.A. Inhibition of GSK3 abolishes bacterial-induced periodontal bone loss in mice.Mol. Med. 2012; 18: 1190-1196Crossref PubMed Scopus (26) Google Scholar, 5Lu L. Yakoumatos L. Ren J. Duan H. et restrains inflammatory responses and periodontal through J. 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Wang et in through of TRAF3 and PubMed Scopus Google Scholar, et of TRAF3 in the and PubMed Scopus Google the anti-inflammatory effect of TRAF3 is on the and the regulatory effect of TRAF3 on oral inflammatory immune on P. gingivalis–induced inflammatory cytokines Y. et Porphyromonas gingivalis and tumor necrosis in through of c-Jun kinase PubMed Scopus Google activation of c-Jun is for P. gingivalis–induced alveolar bone loss through expression of of NF-κB H. I. K. et gingivalis of NF-kappaB expression in through the protein 1 PubMed Scopus Google Scholar). In this our results that SGK1 inhibition significantly expression of we SGK1 the expression of SGK1 has been reported to a variety of and glucocorticoid-regulated protein on a PubMed Scopus Google Scholar). has demonstrated that to of c-Jun in H. K. P. et production by innate immune is by Immunol. 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