Compounds, Targets and Pathways for Macrophage Modulation

Technology

The invention uses a combination of phenotypic screening and transcriptional analysis to identify compounds and their mechanism of action in macrophage activation for new therapies. 

Phenotypic Screening 

• The screening begins with introducing a primary macrophage cell with a candidate agent, which is the agent that is being tested for its ability to have an effect on the cell. For such screening, test compounds can come from various sources such as biochemical compounds (e.g., polysaccharides) and/or biological macromolecules (e.g., peptides, proteins, nucleic acids, extracts made from bacteria, plants, fungi, or animal cells).  

• The screening is performed through high throughput screening assays, in which large numbers of compounds are measured and monitored for their ability to activate different subsets of macrophages. A change in morphology based on the presence of the candidate agent is indictive of its ability to impact macrophage activation. 

• The screened macrophages are monitored and compared to the cell’s morphology in the presence of the candidate agent with the cell’s morphology in the absence of the candidate agent.  

Transcriptional Analysis 

• To validate the identified compounds on macrophage activation, transcriptional analysis by RNA-seq data is performed.  

• The data from studies suggested that the identified compounds reprogram the differentiated macrophages through modulating the expression of genes associated with macrophage activation as well as specific pathways unique to each compound.  

• The resulting data from these identification methods will allow for the distillation of biochemical compounds that can be used to selectively activate macrophages for disease treatments.  

Problem Addressed

A remarkable feature of macrophages is their plasticity, which is the ability to respond to local stimuli to acquire different phenotypes and functions. However, once macrophages adapt to certain microenvironments, the macrophages can end up suppressing immune responses and promote unwanted or harmful growth of other cells. The methods in this invention identify biochemical compounds that can re-program macrophage phenotype and function, which in turn can be used to develop novel therapies for many cancer, metabolic, and infectious diseases. 

Advantages

• Macrophages can acquire different phenotypes and functions to respond to changing physiological needs, while other therapeutic methods may lack this plasticity  

• Macrophages are found in nearly all stages of development, from the fetus through adult life 

• Macrophages are well dispersed in the body and efficiently infiltrate immune cells in certain microenvironments 

Publications

Guangan Hu, et al. High-throughput phenotypic screen and transcriptional analysis identify new compounds and targets for macrophage reprogramming. Nature Communications. 2021 February 2. doi: 10.1038/s41467-021-21066-x

Guangan Hu, et al. Vitamin D3-vitamin D receptor axis suppresses pulmonary emphysema by maintaining alveolar macrophage homeostasis and function. E-Bio Medicine. 2019 July 2. doi: 10.1016/j.ebiom.2019.06.039