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

• Published in: Nature communications 2025-02, Vol.16 (1), p.1342, Article 1342
• Main Authors: Roh, Taylor, Ju, Sungeun, Park, So Young, Ahn, Yeonghwan, Chung, Jiyun, Nakano, Miyako, Ryu, Gyoungah, Kim, Young Jae, Kim, Geumseo, Choi, Hyewon, Lee, Sung-Gwon, Kim, In Soo, Lee, Song-I, Chung, Chaeuk, Shimizu, Takashi, Miyoshi, Eiji, Jung, Sung-Soo, Park, Chungoo, Yamasaki, Sho, Park, Seung-Yeol, Jo, Eun-Kyeong
• Format: Article
• Language: English
• Subjects: 38/47; 38/77; 38/89; 38/90; 38/91; 49/88; 631/250/2504/342; 631/250/256/2516; 631/250/262/2106; 631/80/221; 64/110; 64/60; 692/308/53/2423; 82/58; 82/80; 96/1; 96/21; 96/34; Animal tissues; Biomarkers; Cell activation; Chemokines; Cytokines; Gene sequencing; Glycosylation; Haptoglobin; Hemoglobin; Humanities and Social Sciences; Inflammasomes; Inflammation; Macrophages; multidisciplinary; Observational studies; Prognosis; Receptors; Science; Science (multidisciplinary); Sepsis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-56524-3

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 Haptoglobin (Hp) scavenges cell-free haemoglobin and is associated with the prognosis of human sepsis. Here, the authors characterize the association of fucosylated Hp in sepsis progression and identify a macrophage population expressing a receptor for fucosylated Hp, highlighting its inflammation-amplifying effects in in vitro human cell cultures and in vivo using a mouse model.