Abstract
Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn’s disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn’s disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn’s disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn’s disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner.
Highlights
Leptin has been shown to modulate intestinal inflammation in mice
Leptin has been implicated in the pathogenesis of intestinal inflammation in Crohn’s disease (CD), in which hyperplastic mesenteric fat (“creeping fat”) wraps inflamed small intestinal segments[4], and acts as a source of leptin and additional adipokines, that can modulate both systemic immune cell composition, as well as intestinal epithelial cell function in animal models of colitis[5]
Human data on the immune modulatory effects of leptin are limited to extremely rare diseases including (i) congenital leptin deficiency where T cell hypo-responsiveness, as well as metabolic dysfunction have been shown to be reversible by leptin substitution[16], and (ii) acquired generalized lipodystrophy[17], a condition with approximately 100 known cases worldwide[18]
Summary
Leptin has been shown to modulate intestinal inflammation in mice. clinical evidence regarding its immune-stimulatory potential in human Crohn’s disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn’s disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, aggravating Crohn’s disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Human data on the immune modulatory effects of leptin are limited to extremely rare diseases including (i) congenital leptin deficiency where T cell hypo-responsiveness, as well as metabolic dysfunction have been shown to be reversible by leptin substitution[16], and (ii) acquired generalized lipodystrophy[17], a condition with approximately 100 known cases worldwide[18]. Deep immune profiling by mass and flow cytometry and ex vivo functional assays in addition to clinical assessment before and after rLeptin substitution revealed distinct pro-inflammatory effects of rLeptin treatment that result in an aggravation of intestinal inflammation in a TNFαdependent manner
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