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Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism.

ABSTRACT: The adipocytokine leptin links nutritional status to immune function. Leptin signaling protects from amebiasis, but the molecular mechanism is not understood. We developed an in vitro model of ameba-host cell interaction to test the hypothesis that leptin prevents ameba-induced apoptosis in host epithelial cells. We demonstrated that activation of mammalian leptin signaling increased cellular resistance to amebic cytotoxicity, including caspase-3 activation. Exogenous expression of the leptin receptor conferred resistance in susceptible cells, and leptin stimulation enhanced protection. A series of leptin receptor signaling mutants showed that resistance to amebic cytotoxicity was dependent on activation of STAT3 but not the Src homology-2 domain-containing tyrosine phosphatase (SHP-2) or STAT5. A common polymorphism in the leptin receptor (Q223R) that increases susceptibility to amebiasis in humans and mice was found to increase susceptibility to amebic cytotoxicity in single cells. The Q223R polymorphism also decreased leptin-dependent STAT3 activation by 21% relative to that of the wild-type (WT) receptor (P = 0.035), consistent with a central role of STAT3 signaling in protection. A subset of genes uniquely regulated by STAT3 in response to leptin was identified. Most notable were the TRIB1 and suppressor of cytokine signaling 3 (SOCS3) genes, which have opposing roles in the regulation of apoptosis. Overall apoptotic genes were highly enriched in this gene set (P < 1E-05), supporting the hypothesis that leptin regulation of host apoptotic genes via STAT3 is responsible for protection. This is the first demonstration of a mammalian signaling pathway that restricts amebic pathogenesis and represents an important advance in our mechanistic understanding of how leptin links nutrition and susceptibility to infection.

SUBMITTER: Marie CS

PROVIDER: S-EPMC3347425 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism.

Marie Chelsea S CS Verkerke Hans P HP Paul Shom N SN Mackey Aaron J AJ Petri William A WA

Infection and immunity 20120213 5

The adipocytokine leptin links nutritional status to immune function. Leptin signaling protects from amebiasis, but the molecular mechanism is not understood. We developed an in vitro model of ameba-host cell interaction to test the hypothesis that leptin prevents ameba-induced apoptosis in host epithelial cells. We demonstrated that activation of mammalian leptin signaling increased cellular resistance to amebic cytotoxicity, including caspase-3 activation. Exogenous expression of the leptin re ...[more]

PMID: 22331430

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Project description:UnlabelledAmebiasis is an enteric infection caused by Entamoeba histolytica, with symptoms ranging in severity from asymptomatic colonization to dysentery. Humans with the Q223R leptin receptor mutation have increased susceptibility to amebiasis, but the mechanism has been unclear. Using a mouse model expressing the mutation, we tested the impact of the Q223R mutation on the innate immune response to E. histolytica infection. The 223R mutation resulted in delayed clearance of amebae from the cecum, as had been previously observed. We found that neutrophil influx to the site of the infection was reduced 12 h after infection in 223R mice. Depletion of neutrophils with anti-Ly6G monoclonal antibody increased susceptibility of wild-type mice to infection, supporting the importance of neutrophils in innate defense. Leptin expression was increased in the cecum by E. histolytica infection, suggesting that leptin could serve as a homing signal for neutrophils to the gut. Interestingly, neutrophils from mice with the 223R mutation had diminished chemotaxis toward leptin. This impaired chemotaxis likely explained the reduced gut infiltration of neutrophils. The newly recognized effect of the leptin receptor Q223R mutation on neutrophil chemotaxis and the impact of this mutation on multiple infectious diseases suggest a broader impact of this mutation on susceptibility to disease.ImportanceThe Q223R leptin receptor mutation results in increased susceptibility of children and adults to E. histolytica, one of the leading causes of diarrhea morbidity and mortality in children of the developing world. Here we show that the mutation results in reduced neutrophil infiltration to the site of infection. This decreased infiltration is likely due to the mutation's impact on neutrophil chemotaxis toward leptin, an inflammatory agent upregulated in the cecum after infection. The significance of this work thus extends beyond understanding E. histolytica susceptibility by also providing insight into the potential impact of leptin on neutrophil function in other states of altered leptin signaling, which include both malnutrition and obesity.

Dataset Information

Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism.

Publications

Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism.

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