RT Journal Article
SR Electronic
T1 Acidosis, Zinc and HMGB1 in Sepsis: A Common Connection Involving Sialoglycan Recognition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.15.198010
DO 10.1101/2020.07.15.198010
A1 Shoib S. Siddiqui
A1 Chirag Dhar
A1 Venkatasubramaniam Sundaramurthy
A1 Aniruddha Sasmal
A1 Hai Yu
A1 Esther Bandala-Sanchez
A1 Miaomiao Li
A1 Xiaoxiao Zhang
A1 Xi Chen
A1 Leonard C. Harrison
A1 Ding Xu
A1 Ajit Varki
YR 2020
UL http://biorxiv.org/content/early/2020/07/15/2020.07.15.198010.abstract
AB Blood pH is tightly regulated between 7.35-7.45, with values below 7.3 during sepsis being associated with lactic acidosis, low serum zinc, and release of proinflammatory HMGB1 from activated and/or necrotic cells. Using an ex vivo whole blood system to model lactic acidosis, we show that while HMGB1 does not engage leukocyte receptors at physiological pH, lowering pH with lactic acid facilitates binding. At normal pH, micromolar zinc supports plasma sialoglycoprotein binding by HMGB1, which is markedly reduced when pH is adjusted with lactic acid to sepsis levels. Glycan array studies confirmed zinc and pH-dependent HMGB1 binding to sialoglycans typical of plasma glycoproteins. Thus, proinflammatory effects of HMGB1 are suppressed via plasma sialoglycoproteins until drops in pH and zinc release HMGB1 to trigger downstream immune activation.Significance Statement HMGB1 sequestered by plasma sialoglycoproteins at physiological pH is released when pH and zinc concentrations fall in sepsis.Competing Interest StatementThe authors have declared no competing interest.