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Nat Commun. 2025 Feb 4;16(1):1342.

Title : Fucosylated haptoglobin promotes inflammation via Mincle in sepsis: an observational study

Authors : Taylor Roh#1,2,3, Sungeun Ju#4, So Young Park#5, Yeonghwan Ahn4, Jiyun Chung4, Miyako Nakano6, Gyoungah Ryu1,2, Young Jae Kim1,2,3, Geumseo Kim1,2,3, Hyewon Choi4, Sung-Gwon Lee7, In Soo Kim2,3,8, Song-I Lee9, Chaeuk Chung10, Takashi Shimizu11,12, Eiji Miyoshi13, Sung-Soo Jung14, Chungoo Park15, Sho Yamasaki11,12,16, Seung-Yeol Park17*, Eun-Kyeong Jo18,19*

Affiliations :

1Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

2Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

3Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

4Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.

5Division of Pulmonary, Allergy and Critical Care Medicine, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea. sy.park12@gmail.com.

6Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.

7Section of Genetics and Physiology, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.

8Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

9Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.

10Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

11Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.

12Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan.

13Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

14Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

15School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.

16Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, Japan.

17Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.

18Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

19Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

DOI: 10.1038/s41467-025-56524-3.

Abstract :

Haptoglobin (Hp) scavenges cell-free hemoglobin and correlates with the prognosis of human sepsis, a life-threatening systemic inflammatory condition. Despite extensive research on Hp glycosylation as a glyco-biomarker for cancers, understanding glycosylated modifications of Hp in sepsis patients (SPs) remains limited. Our study reveals elevated levels of terminal fucosylation at Asn207 and Asn211 of Hp in SP plasma, along with heightened inflammatory responses, compared to healthy controls (trial registration NCT05911711). Fucosylated (Fu)-Hp purified from SPs upregulates inflammatory cytokines and chemokines, along with NLRP3 inflammasome activation. Single-cell RNA sequencing identifies a distinct macrophage-like cell population with increased expressions of inflammatory mediators and FUT4 in response to Fu-Hp. Additionally, Mincle, a C-type lectin receptor, interacts with Fu-Hp to amplify the inflammatory responses and signaling. Moreover, the Hp fucosylation (AAL) level significantly correlates with the levels of inflammatory cytokines in sepsis patients, suggesting that Fu-Hp is clinically relevant. Finally, Fu-Hp treatment significantly enhances the levels of inflammatory cytokines in the plasma and various tissues of mice. Together, our findings reveal a role of Fu-Hp, derived from sepsis patients, in driving inflammation, and suggest that targeting Fu-Hp could serve as a promising intervention for combating sepsis. Trial registration NCT05911711.