Selective Nanotherapeutic Targeting of the Neutrophil Subset Mediating Inflammatory Injury

Bachmaier, Kurt; Stuart, Andrew; Hong, Zhigang; Tsukasaki, Yoshikazu; Singh, Abhalaxmi; Chakraborty, Sreeparna; Mukhopadhyay, Amitabha; Gao, Xiaopei; Maienschein-Cline, Mark; Kanteti, Prasad; Rehman, Jalees; Malik, Asrar B.

Inflammatory tissue injury such as acute lung injury (ALI) is a disorder that leads to respiratory failure, a major cause of morbidity and mortality worldwide. Excessive neutrophil influx is a critical pathogenic factor in the development of ALI. Here, we identify the subset of neutrophils that is responsible for ALI and lethality in polymicrobial sepsis. The pro-inflammatory neutrophil subpopulation was characterized by its unique ability to endocytose albumin nanoparticles (ANP), upregulation of pro-inflammatory cytokines and chemokines as well as the excessive production of reactive oxygen species (ROS) in models of endotoxemia and septicemia. ANP delivery of the drug piceatannol, a spleen tyrosine kinase (Syk) inhibitor, to the susceptible subset of neutrophils, prevented ALI and mortality in mice subjected to polymicrobial infection. Targeted inhibition of Syk in ANP-susceptible neutrophils had no detrimental effect on neutrophil-dependent host defense because the subset of ANPlow neutrophils effectively controlled polymicrobial infection. The results show that neutrophil heterogeneity can be leveraged therapeutically to prevent ALI without compromising host defense.