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

Taylor Roh, Sungeun Ju, So Young Park (), Yeonghwan Ahn, Jiyun Chung, Miyako Nakano, Gyoungah Ryu, Young Jae Kim, Geumseo Kim, Hyewon Choi, Sung-Gwon Lee, In Soo Kim, Song-I Lee, Chaeuk Chung, Takashi Shimizu, Eiji Miyoshi, Sung-Soo Jung, Chungoo Park, Sho Yamasaki, Seung-Yeol Park () and Eun-Kyeong Jo ()
Additional contact information
Taylor Roh: Chungnam National University
Sungeun Ju: Pohang University of Science and Technology (POSTECH)
So Young Park: Kangdong Sacred Heart Hospital
Yeonghwan Ahn: Pohang University of Science and Technology (POSTECH)
Jiyun Chung: Pohang University of Science and Technology (POSTECH)
Miyako Nakano: Higashi-Hiroshima
Gyoungah Ryu: Chungnam National University
Young Jae Kim: Chungnam National University
Geumseo Kim: Chungnam National University
Hyewon Choi: Pohang University of Science and Technology (POSTECH)
Sung-Gwon Lee: National Institutes of Health (NIH)
In Soo Kim: Chungnam National University
Song-I Lee: Chungnam National University Hospital
Chaeuk Chung: Chungnam National University
Takashi Shimizu: Suita
Eiji Miyoshi: Suita
Sung-Soo Jung: Chungnam National University
Chungoo Park: Chonnam National University
Sho Yamasaki: Suita
Seung-Yeol Park: Pohang University of Science and Technology (POSTECH)
Eun-Kyeong Jo: Chungnam National University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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

Date: 2025
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DOI: 10.1038/s41467-025-56524-3

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