Altered microbiota by a high-fat diet accelerates lethal myeloid hematopoiesis associated with systemic SOCS3 deficiency

Kaori Cho; Takashi Ushiki; Hajime Ishiguro; Suguru Tamura; Masaya Araki; Tatsuya Suwabe; Takayuki Katagiri; Mari Watanabe; Yoko Fujimoto; Riuko Ohashi; Yoichi Ajioka; Ippei Shimizu; Shujiro Okuda; Masayoshi Masuko; Yoshimi Nakagawa; Hideyo Hirai; Warren S Alexander; Hitoshi Shimano; Hirohito Sone

doi:10.1016/j.isci.2021.103117

Altered microbiota by a high-fat diet accelerates lethal myeloid hematopoiesis associated with systemic SOCS3 deficiency

iScience. 2021 Sep 11;24(10):103117. doi: 10.1016/j.isci.2021.103117. eCollection 2021 Oct 22.

Authors

Kaori Cho¹, Takashi Ushiki^{1

2}, Hajime Ishiguro¹, Suguru Tamura¹, Masaya Araki³, Tatsuya Suwabe¹, Takayuki Katagiri¹, Mari Watanabe², Yoko Fujimoto², Riuko Ohashi^{4

5}, Yoichi Ajioka^{4

5}, Ippei Shimizu⁶, Shujiro Okuda⁷, Masayoshi Masuko¹, Yoshimi Nakagawa⁸, Hideyo Hirai^{9

10}, Warren S Alexander^{11

12}, Hitoshi Shimano³, Hirohito Sone¹

Affiliations

¹ Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Niigata 951-8510, Japan.
² Department of Transfusion Medicine, Cell Therapy and Regenerative Medicine, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata, Niigata 951-8520, Japan.
³ Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
⁴ Histopathology Core Facility, Faculty of Medicine, Niigata University, Niigata, Niigata 951-8510, Japan.
⁵ Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951-8510, Japan.
⁶ Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
⁷ Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951-8510, Japan.
⁸ Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.
⁹ Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Kyoto 606-8507, Japan.
¹⁰ Laboratory of Stem Cell Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
¹¹ Blood Cells and Blood Cancer Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
¹² Department of Medical Biology, the University of Melbourne, Parkville, VIC 3052, Australia.

Abstract

The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD.

Keywords: immunology; microbiome.