TY - JOUR
T1 - Distinct immunomodulatory effects of spermine oxidase in colitis induced by epithelial injury or infection
AU - Gobert, Alain P.
AU - Al-Greene, Nicole T.
AU - Singh, Kshipra
AU - Coburn, Lori A.
AU - Sierra, Johanna C.
AU - Verriere, Thomas G.
AU - Luis, Paula B.
AU - Schneider, Claus
AU - Asim, Mohammad
AU - Allaman, Margaret M.
AU - Barry, Daniel P.
AU - Cleveland, John L.
AU - Shields, Christina E.Destefano
AU - Casero, Robert A.
AU - Washington, M. Kay
AU - Piazuelo, M. Blanca
AU - Wilson, Keith T.
N1 - Funding Information:
This work was funded by NIH grants R01AT004821, R01CA190612, P01CA116087, P01CA028842 (KW), RO1CA204345 (RC); Maryland Cigarette Restitution Fund (RC); Veterans Affairs Merit Review grant I01BX001453 (KW); the Thomas F Frist Sr. Endowment (KW); and the Vanderbilt Center for Mucosal Inflammation and Cancer (KW). LC was supported by Veterans Affairs Career Development Award 1IK2BX002126. This work was supported by NIH awards AT006896 by NCCIH (CS and PL) was supported by a postdoctoral fellowship award from the American Heart Association (16POST27250138). Mass spectrometric analyses were in part performed through Vanderbilt University Medical Center's Digestive Disease Research Center supported by NIH grant P30DK058404 Core Scholarship.
Publisher Copyright:
© 2018 Gobert, Al-Greene, Singh, Coburn, Sierra, Verriere, Luis, Schneider, Asim, Allaman, Barry, Cleveland, Destefano Shields, Casero, Washington, Piazuelo and Wilson.
PY - 2018/6/5
Y1 - 2018/6/5
N2 - Polyamines have been implicated in numerous biological processes, including inflammation and carcinogenesis. Homeostatic regulation leads to interconversion of the polyamines putrescine and the downstream metabolites spermidine and spermine. The enzyme spermine oxidase (SMOX), which back-converts spermine to spermidine, contributes to regulation of polyamine levels, but can also have other effects. We have implicated SMOX in gastric inflammation and carcinogenesis due to infection by the pathogen Helicobacter pylori. In addition, we reported that SMOX can be upregulated in humans with inflammatory bowel disease. Herein, we utilized Smox-deficient mice to examine the role of SMOX in two murine colitis models, Citrobacter rodentium infection and dextran sulfate sodium (DSS)-induced epithelial injury. In C. rodentium-infected wild-type (WT) mice, there were marked increases in colon weight/length and histologic injury, with mucosal hyperplasia and inflammatory cell infiltration; these changes were ameliorated in Smox-/- mice. In contrast, with DSS, Smox-/- mice exhibited substantial mortality, and increased body weight loss, colon weight/length, and histologic damage. In C. rodentium-infected WT mice, there were increased colonic levels of the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10, and the cytokines IL-6, TNF-α, CSF3, IFN-γ, and IL-17; each were downregulated in Smox-/- mice. In DSS colitis, increased levels of IL-6, CSF3, and IL-17 were further increased in Smox-/- mice. In both models, putrescine and spermidine were increased in WT mice; in Smox-/- mice, the main effect was decreased spermidine and spermidine/spermine ratio. With C. rodentium, polyamine levels correlated with histologic injury, while with DSS, spermidine was inversely correlated with injury. Our studies indicate that SMOX has immunomodulatory effects in experimental colitis via polyamine flux. Thus, SMOX contributes to the immunopathogenesis of C. rodentium infection, but is protective in DSS colitis, indicating the divergent effects of spermidine.
AB - Polyamines have been implicated in numerous biological processes, including inflammation and carcinogenesis. Homeostatic regulation leads to interconversion of the polyamines putrescine and the downstream metabolites spermidine and spermine. The enzyme spermine oxidase (SMOX), which back-converts spermine to spermidine, contributes to regulation of polyamine levels, but can also have other effects. We have implicated SMOX in gastric inflammation and carcinogenesis due to infection by the pathogen Helicobacter pylori. In addition, we reported that SMOX can be upregulated in humans with inflammatory bowel disease. Herein, we utilized Smox-deficient mice to examine the role of SMOX in two murine colitis models, Citrobacter rodentium infection and dextran sulfate sodium (DSS)-induced epithelial injury. In C. rodentium-infected wild-type (WT) mice, there were marked increases in colon weight/length and histologic injury, with mucosal hyperplasia and inflammatory cell infiltration; these changes were ameliorated in Smox-/- mice. In contrast, with DSS, Smox-/- mice exhibited substantial mortality, and increased body weight loss, colon weight/length, and histologic damage. In C. rodentium-infected WT mice, there were increased colonic levels of the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10, and the cytokines IL-6, TNF-α, CSF3, IFN-γ, and IL-17; each were downregulated in Smox-/- mice. In DSS colitis, increased levels of IL-6, CSF3, and IL-17 were further increased in Smox-/- mice. In both models, putrescine and spermidine were increased in WT mice; in Smox-/- mice, the main effect was decreased spermidine and spermidine/spermine ratio. With C. rodentium, polyamine levels correlated with histologic injury, while with DSS, spermidine was inversely correlated with injury. Our studies indicate that SMOX has immunomodulatory effects in experimental colitis via polyamine flux. Thus, SMOX contributes to the immunopathogenesis of C. rodentium infection, but is protective in DSS colitis, indicating the divergent effects of spermidine.
KW - Colitis
KW - Infection
KW - Mucosal immune response
KW - Polyamines
KW - Spermidine
KW - Spermine oxidase
UR - http://www.scopus.com/inward/record.url?scp=85048094720&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048094720&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2018.01242
DO - 10.3389/fimmu.2018.01242
M3 - Article
C2 - 29922289
AN - SCOPUS:85048094720
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JUN
M1 - 1242
ER -