Acidosis, Zinc and HMGB1 in Sepsis: A Common Connection Involving Sialoglycan Recognition

Siddiqui, Shoib S.; Dhar, Chirag; Sundaramurthy, Venkatasubramaniam; Sasmal, Aniruddha; Yu, Hai; Bandala-Sanchez, Esther; Li, Miaomiao; Zhang, Xiaoxiao; Chen, Xi; Harrison, Leonard C.; Xu, Ding; Varki, Ajit

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.