Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia

Choi, Sun Mi; McAleer, Jeremy P.; Zheng, Mingquan; Pociask, Derek; Kaplan, Mark H.; Qin, Shulin; Reinhart, Todd A.; Kolls, Jay K.

doi:10.1084/jem.20120260

Cited by 102 publications

(104 citation statements)

References 32 publications

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“…5C), suggesting a cell type-specific role of rapamycin in regulation of inflammation-induced Stat3 activation. In accord with the hyperactivation of Stat3 in colonic epithelium in WT mice upon DSS treatment, we observed a significant elevation of the mRNA expression level of the Stat3 target gene Reg3g, which is important for antimicrobial activity (33). However, Rheb +/2 mice had a much lower induction of Reg3g, which is the direct target of Stat3, suggesting that Stat3 signaling was impaired in Rheb +/2 mice during colitis (Fig.…”

Section: Stat3 Activity Is Inhibited In Mtorc1-deficient Mice During supporting

confidence: 75%

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

Guan

Zhang

et al. 2015

The Journal of Immunology

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The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues to regulate cell growth and survival through various mechanisms. However, how mTORC1 responds to acute inflammatory signals to regulate bowel regeneration is still obscure. In this study, we investigated the role of mTORC1 in acute inflammatory bowel disease. Inhibition of mTORC1 activity by rapamycin treatment or haploinsufficiency of Rheb through genetic modification in mice impaired intestinal cell proliferation and induced cell apoptosis, leading to high mortality in dextran sodium sulfate– and 2,4,6-trinitrobenzene sulfonic acid–induced colitis models. Through bone marrow transplantation, we found that mTORC1 in nonhematopoietic cells played a major role in protecting mice from colitis. Reactivation of mTORC1 activity by amino acids had a positive therapeutic effect in mTORC1-deficient Rheb+/− mice. Mechanistically, mTORC1 mediated IL-6–induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity. As mTORC1 is an important therapeutic target for multiple diseases, our findings will have important implications for the clinical usage of mTORC1 inhibitors in patients with acute inflammatory bowel disease.

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Section: Stat3 Activity Is Inhibited In Mtorc1-deficient Mice During supporting

confidence: 75%

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

Guan

Zhang

et al. 2015

The Journal of Immunology

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“…Moreover, STAT3 activation has been associated with Reg3b and Reg3g synthesis in intestinal and lung epithelia, respectively (36,37): thus, we considered the possibility that CDCA would act over AMPP synthesis by activation of STAT3 either directly or through the induction of IL-6. In fact, activation of STAT3 using IL-6 in rat IEC-6/L1 intestinal epithelial cells and mouse explants correlated with increased production of Reg3b (Fig.…”

Section: Resultsmentioning

confidence: 99%

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

et al. 2017

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In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell ␣-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or ␤-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal Muc2 and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G ϩ and CD68 ϩ cells, while increasing the relative amount of IgG ϩ B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections.

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“…IL-22 has been shown to play a critical role in mucosal immunity at barrier surfaces, including the gastrointestinal tract and in the lung (24). In the gut, IL-22 regulates the expression of antimicrobial proteins, such as Reg3␥ (25), and can also increase fucosylation through the upregulation of Fut2, resulting in enhanced resistance to pathogens (26)(27)(28). IL-22 can also activate STAT1 and increase antiviral immunity in the gut (23).…”

Section: Discussionmentioning

confidence: 99%

“…IL-22 can also activate STAT1 and increase antiviral immunity in the gut (23). In the lung, IL-22 can induce the expression of Reg3g (25) and Lcn2 (10), which can mediate host resistance against certain Gram-positive and Gram-negative bacteria, respectively. Based on some of these activities and its protection against epithelial damage, IL-22 is in a clinical trial for gut-related graft-versus-host disease (ClinicalTrials registration no.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

et al. 2016

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Hep؊/؊ ) and Stat3 knockout (Stat3 Hep؊/؊ ) mice were generated and subjected to intra-abdominal infection with Klebsiella pneumoniae, which results in liver injury and necrosis. We found that overexpression of IL-22 or therapeutic administration of recombinant IL-22 (rIL-22), given 2 h postinfection, significantly reduced the bacterial burden in both the liver and spleen. The antimicrobial activity of rIL-22 required hepatic Il22Ra1 and Stat3. Serum from rIL-22-treated mice showed potent bacteriostatic activity against K. pneumoniae, which was dependent on lipocalin 2 (LCN2). However, in vivo, rIL-22-induced antimicrobial activity was only partially reduced in LCN2-deficient mice. We found that rIL-22 also induced serum amyloid A2 (SAA2) and that SAA2 had anti-K. pneumoniae bactericidal activity in vitro. These results demonstrate that IL-22, through IL-22Ra1 and STAT3 singling, can induce intrinsic antimicrobial activity in the liver, which is due in part to LCN2 and SAA2. Therefore, IL-22 may be a useful adjunct in treating hepatic and intra-abdominal infections.

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Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia

Abstract: STAT3-mediated induction of Reg3γ enhances bacteriostatic and bactericidal activity to pulmonary Staphylococcus aureus.

Cited by 102 publications

References 32 publications

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

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