Sialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsis
Shoib S Siddiqui, Chirag Dhar, Venkatasubramaniam Sundaramurthy, Aniruddha Sasmal, Hai Yu, Esther Bandala-Sanchez, Miaomiao Li, Xiaoxiao Zhang, Xi Chen, Leonard C Harrison, Ding Xu, Ajit Varki
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2021
Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated..View full abstract
Awarded by NIH
We thank Sandra Diaz and Patrick Secrest for their excellent technical help with the work. Fig. 6 was created using https://biorender.com/.This work was supporting by NIH Grants R01GM32373 (to A.V.) and R01AR070179 and R01HL094463 (to D.X.).