Macrophage WNK1 senses intracellular hypo-chlorine to regulate vulnerability to sepsis attack during hypochloremia

Sepsis is one of the leading causes of death in critical patients worldwide and its occurrence is related to the excessive activation of macrophages. Chloride loss worsens the prognosis of patients with sepsis but the underlying mechanism is currently unclear. In this study, we founded that macrophages deficient in intracellular Cl^- secrete more inflammatory cytokines such as IL-1β, IL-6 and TNF-α compared with control group. The intracellular chloride level decreased in WNK1 deficiency or activity inhibited macrophages with more severe inflammatory response after LPS treatment. Remimazolam, as classic GABAa receptor agonist, alleviates excessive inflammation cascade by promoting macrophage chloride influx during sepsis progression. Collectively, this study proves that macrophage WNK1 acts as a negative regulator of inflammatory response by sensing chloride to maintain intracellular chloride balance during sepsis coupled with hypochloremia.