Integrin activation by two independently regulated calcium-mediated pathways is required for neutrophil recruitment

Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency syndrome in humans, characterized by reduced leukocyte recruitment. The regulation of intracellular calcium levels in neutrophils is important for cellular processes; however, the exact role of store-operated calcium entry (SOCE) and the involvement of stromal interaction molecule (STIM) calcium sensors, and ORAI1-3 calcium channels in neutrophil activation and recruitment is unknown.

Using an acute kidney injury (AKI) model, intravital microscopy, and biochemical studies, we examined the molecular mechanisms of Ca²⁺-regulated neutrophil activation and recruitment.

We demonstrate that STIM1 and ORAI1 in neutrophils are selectively required for E-selectin- and CXCL-1-, but not P-selectin-mediated activation of the β₂-integrin CD11a and neutrophil recruitment. Surprisingly, we did not detect an impact of STIM and ORAI isoform expression on neutrophil CD11b activation. Using a clinically relevant murine AKI model, we point out that STIM1- and ORAI1-deficiency in neutrophils prevents neutrophil recruitment into the kidney during sterile inflammation.

Thus, we uncover stimulus specific integrin regulation in neutrophils as a critical determinant of an adequate immune response and pinpoint the clinical relevance of STIM1 and ORAI1.