Neutrophil heterogeneity in immune regulation

About This Grant

Project Summary Neutrophils play a critical role in innate immunity and host defense against invading microorganisms, but also contribute pathogenically to a number of non-infectious conditions including asthma, multiple sclerosis, rheumatoid arthritis, gastritis, inflammatory bowel disease, cancer, and ischemia-induced tissue damage. Disentangling the beneficial and harmful activities of neutrophils has proven exceptionally difficult, as they present with varied and often opposing physiological functions that are influenced by the timing and location of the inflammatory response. Recent studies have revealed that neutrophils are not a homogeneous cell population; instead, they display a diverse array of functional states, phenotypes, and lifespans. This offers an opportunity to develop tailored therapeutic strategies by targeting distinct neutrophil subsets or inducing specific functional states in neutrophils. The theme of this project is to uncover the nature and function of neutrophil heterogeneity, a fundamental question in neutrophil biology. The hypothesis is that the neutrophil compartment is a collection of cell phenotypes, states, and sub-lineages capable of distinct functions. Understanding how these subpopulations arise and function will define new targets for neutrophil manipulation, establishing specific lineages as vehicles for clinical intervention. Dr. Luo (Project 1) will investigate the origin and characterize the functional state of lung interstitial neutrophils (LINs). Dr. Mayadas (Project 2) will investigate the origin, regulation and trafficking of a subset of spleen-derived neutrophils that acquire antigen- presenting cell (nAPCs) properties following engagement of their FcγRs. Dr. Nigrovic (Project 3) will test the hypothesis that emperipolesis of neutrophils by megakaryocytes in the bone marrow modulates the phenotype of neutrophils and thereby drives neutrophil heterogeneity. Finally, Dr. Hidalgo (Project 4) will evaluate the hypothesis that neutrophils with antimicrobial and inflammatory properties have different origins and will further characterize the properties and origin of neutrophils that mediate inflammation. The four research projects will be bolstered by a unique centralized Bioinformatics Core led by Andres Hidalgo, which is particularly valuable in this collaborative research project as it will enhance data quality, accessibility to expertise, efficiency, collaboration potential, and overall scientific rigor. An Administrative Core led by Hongbo Luo will coordinate and direct the collaborative, multi-disciplinary, interactive, and synergistic research activities of these projects and cores to create a cohesive unit. Collectively, the four projects proposed here, supported by the two cores, will work together to form a unified and productive program to comprehensively elucidate the origin and cellular mechanisms driving the heterogeneity of neutrophils and their reprogramming in health and disease. This work will lay the foundation for neutrophil subset-specific therapeutic strategies in the treatment of infectious and inflammatory diseases.