Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease.,Nature Communications

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Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease.
Nature Communications ( IF 14.7 ) Pub Date : 2019-12-10 , DOI: 10.1038/s41467-019-13559-7
Jörn F Ziegler _{1,

2} , Chotima Böttcher _{1,

3} , Marilena Letizia _{1,

2} , Cansu Yerinde _{1,

2} , Hao Wu _{1,

2} , Inka Freise _{1,

2} , Yasmina Rodriguez-Sillke _{1,

2} , Ani K Stoyanova _{1,

4} , Martin E Kreis _{1,

4} , Patrick Asbach _{1,

5} , Desiree Kunkel _{1,

6} , Josef Priller _{1,

3,

7} , Ioannis Anagnostopoulos _{1,

8} , Anja A Kühl _{1,

9} , Konstanze Miehle ₁₀ , Michael Stumvoll ₁₀ , Florian Tran ₁₁ , Broder Fredrich ₁₁ , Michael Forster ₁₁ , Andre Franke ₁₁ , Christian Bojarski _{1,

2} , Rainer Glauben _{1,

2} , Britt-Sabina Löscher ₁₁ , Britta Siegmund _{1,

2} , Carl Weidinger _{1,

2,

12}

Affiliation

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany.
Laboratory of Molecular Psychiatry and Department of Neuropsychiatry, Berlin, Germany.
Department of Visceral Surgery, Campus Benjamin Franklin, Berlin, Germany.
Department of Radiology, Campus Benjamin Franklin, Berlin, Germany.
BIH Cytometry Core, Berlin Institute of Health, 10178, Berlin, Germany.
BIH Berlin, DZNE Berlin and University of Edinburgh and UK DRI, Edinburgh, UK.
Department of Pathology, Campus Charité Mitte, Berlin, Germany.
iPATH.Berlin-Immunopathology for Experimental Models, Core Facility of the Charité, Berlin, Germany.
Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Clinician Scientist Program, Berlin Institute of Health, Berlin, Germany.

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.

中文翻译：

瘦素在获得性全身脂肪营养不良和合并的克罗恩病中诱导TNFα依赖性炎症。

瘦素已被证明可调节小鼠的肠道炎症。然而，关于其在人类克罗恩病中的免疫刺激潜力的临床证据仍然很少。我们在这里描述的患者具有获得性泛发性脂肪营养不良和克罗恩病（AGLCD）的独特组合，其特征是缺乏脂肪组织，瘦素缺乏和肠道炎症。使用质量和流式细胞仪，免疫组织化学和功能代谢分析，将AGLCD患者与健康个体和克罗恩病患者的免疫细胞组成，功能和代谢进行了比较，并评估了重组N-甲硫基肽素（rLeptin）的作用。我们提供的证据表明rLeptin对免疫细胞的分化和功能具有多种促炎作用，包括免疫细胞的代谢重编程和TNFα的诱导，最终加重了AGLCD患者的克罗恩氏病，可以通过抗TNFα疗法逆转。我们的结果表明，瘦素是人体免疫稳态所必需的，并以TNFα依赖性方式促进自身免疫。

更新日期：2019-12-11

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