Fucosylated haptoglobin promotes inflammation via Mincle in sepsis: an observational study
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.
Authors
- G. Kim (ORCID: https://orcid.org/0000-0002-6847-5155)
- Sungeun Ju (ORCID: https://orcid.org/0000-0002-8597-3850)
- Sung‐Gwon Lee (ORCID: https://orcid.org/0000-0002-0928-9950)
- Chaeuk Chung (ORCID: https://orcid.org/0000-0002-3978-0484)
- Song‐I Lee (ORCID: https://orcid.org/0000-0001-8372-4511)
- Ju‐Young Chung (ORCID: https://orcid.org/0000-0003-4162-5317)
- Gyoungah Ryu
- Chungoo Park (ORCID: https://orcid.org/0000-0002-9545-6654)
- Yeonghwan Ahn
- Eun‐Kyeong Jo (ORCID: https://orcid.org/0000-0001-7191-0587)
- Takashi Shimizu (ORCID: https://orcid.org/0000-0003-1294-0799)
- Taylor Roh (ORCID: https://orcid.org/0000-0002-6399-1257)
- Eiji Miyoshi (ORCID: https://orcid.org/0000-0002-9430-2362)
- Sung Soo Jung (ORCID: https://orcid.org/0000-0001-7990-3066)
- So Young Park (ORCID: https://orcid.org/0000-0003-4544-2462)
- In Soo Kim
- Young Jae Kim (ORCID: https://orcid.org/0000-0003-0035-037X)
- Sho Yamasaki (ORCID: https://orcid.org/0000-0002-5184-6917)
- Hyewon Choi (ORCID: https://orcid.org/0000-0002-3476-9411)
- Seung‐Yeol Park (ORCID: https://orcid.org/0000-0001-5061-4535)
- Miyako Nakano
Institutions
- Chonnam National University (KR)
- Hiroshima University (JP)
- Pohang University of Science and Technology (KR)
- National Institutes of Health (US)
- Chungnam National University (KR)
- Sacred Heart Hospital (IE)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- National University College (PR)
- Chungnam National University Hospital (KR)
- Kangdong Sacred Heart Hospital (KR)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1038/s41467-025-56524-3
- Citations
- 7
- Primary Topic
- Hemoglobin structure and function
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- National Research Foundation
- Korea Health Industry Development Institute
- National Research Foundation of Korea
- Ministry of Science and ICT, South Korea
- Samsung Science and Technology Foundation
- Samsung