Newly discovered neutrophil subset-specific targeted therapy for human inflammatory diseases


Neutrophils are the most abundant type of white blood cells. In healthy adults, they typically constitute about 50 to 70 percent of white blood cells and function as the first line of defense against bacteria and other foreign organisms. Neutrophils also participate as mediators of inflammation in diseases like arthritis or Crohn’s disease, or excessive inflammation, like sepsis, the role of neutrophils may be deleterious. Neutrophils have been described in research as also contributing to tissue damage—the double-edged sword of inflammation. Unfortunately, current drugs for inflammatory diseases that target neutrophils suppress all their effects, including their anti-infection and healing functions. Understanding the differences between these neutrophil subsets opens the door for more research on treatments that address inflammatory diseases without increasing patients’ risks of infections

In a new study  by scientists at the University of Illinois Chicago, they designed albumin nanoparticle  that can recognize two distinct subtypes of neutrophils and found that one of the subtypes can be used as a drug target for inflammatory diseases.  By leveraging ANP endocytosis for a molecular characterization of neutrophil subsets, the authors established signature functional and phenotypic profiles of the neutrophil subset. Furthermore, subset-specific therapeutic targeting proved to be highly effective in ameliorating inflammatory tissue injury. The original research article is now published in ACS Nano, a scientific publication of the American Chemical Society.

The research team used the albumin- based nanoparticle platform to analyze how neutrophils from bone marrow, blood, and spleen and lung tissues interact with the nanoparticle. They found that some neutrophils brought the albumin nanoparticle into the cell via endocytosis, while others didn’t. The scientists labeled the subtype that readily endocytosed the nanoparticle as ANP-high, for albumin nanoparticle high. The neutrophils that did not absorb the albumin nanoparticle were labeled as ANP-low. Further investigation with the albumin nanoparticle showed that the subtypes have different cell surface receptors and that they are functionally distinct in their helpful capacities to kill bacteria and their harmful potential to promote inflammation. ANP-high neutrophils did not help to kill bacteria but produced inordinate amounts of reactive oxygen species and inflammatory chemokines and cytokines, which contribute to inflammatory disease.

Because the ANP-high neutrophils are also the ones that captured the nanoparticle, the authors used albumin nanoparticle to deliver drug treatments. They filled the nanoparticle with an anti-inflammatory drug and administered it to mice with sepsis. They found that the mice treated with the drug-loaded nanoparticle had reduced signs of tissue inflammation, but that the neutrophilic host-defense was preserved. The new study opens the possibility of using neutrophil subset-specific targeted therapy for human inflammatory diseases

Newly discovered neutrophil subset-specific targeted therapy for human inflammatory diseases - Medicine Innovates

About the author

Asrar B Malik, PhD
Schweppe Family Distinguished Professor
Department Head, Pharmacology
University of Illinois at Chicago

Research Interests

We are pursuing studies in three related areas: A major interest of the laboratory is to understand the regulation of the barrier properties of endothelial and epithelial cells. Dr. Malik’s laboratory studies the events that occur at the level of receptors and the signaling pathways that regulate the barrier function of these monolayers. As thrombin has been shown to increase endothelial permeability, we are studying, using this agonist, how the activation of its proteolytically cleaved receptor leads to the observed increase in permeability. Studies have localized the domains of the receptor involved in both activation and inactivation of endothelial cell signaling. Researchers are exploring ways to inhibit the thrombin-induced barrier dysfunction by such as by introducing dominant negative forms of the receptor to inhibit thrombin receptor activation. Studies are also characterizing cellular effector pathways that increase vascular permeability to understand how the activation of the signaling pathways mobilizes these effectors (i.e., actin-myosin motor, cadherin-catenin complex and the intermediate cytoskeletal filaments).

An additional objective of the laboratory is to develop and test novel strategies for drug delivery. We are specifically interested in targeting cells of the vessel wall which are critical in the pathogenesis of inflammatory diseases, atherosclerosis, and cancer metastasis. The intent is to prevent, in a specific manner, the expression of endothelial adhesion molecules. Among the approaches being studied include the selective expression, using inducible promoters target the expression of “anti-adhesive” proteins in endothelial cells. We are also developing non-viral means including nanoparticles of delivery to transduce endothelial proteins of interest. The approaches taken involve molecular biology as well as physiological monitoring in genetic mouse models.


Kurt Bachmaier, Andrew Stuart, Abhalaxmi Singh, Amitabha Mukhopadhyay, Sreeparna Chakraborty, Zhigang Hong, Li Wang, Yoshikazu Tsukasaki, Mark Maienschein-Cline, Balaji B. Ganesh, Prasad Kanteti, Jalees Rehman, and Asrar B. Malik. Albumin Nanoparticle Endocytosing Subset of Neutrophils for Precision Therapeutic Targeting of Inflammatory Tissue Injury. ACS Nano 2022, 16, 3, 4084–4101

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