Inhibition of Stat3 and inflammatory cytokine production

Hospital For Special Surgery, New York NY

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Macrophages polarize in response to environmental cues to assume specific phenotypes important for tissue homeostasis, host defense, and adaptation to injury and stress. Macrophage polarization also occurs in chronic inflammatory disorders and tumors and is an important driver of disease pathology. The long term goals of this project are to understand how macrophage polarization is regulated and how the polarized state affects macrophage responses to their environment to impact innate immunity and inflammatory responses. An associated goal is to use this knowledge to therapeutically modulate macrophage polarization to optimize host defense while minimizing inflammation-associated pathology. Recently, the importance of epigenetic mechanisms and cellular metabolism in macrophage polarization are increasingly appreciated. Epigenetics and metabolism share the ability to shape macrophage responses to their environment, are important emerging areas in macrophage research, and are linked mechanistically as epigenetic regulators utilize products of metabolic enzymes. IFN-?, often in combination with microbial products such as TLR ligands, polarizes macrophages towards an `M1' classical activation phenotype that is characterized by increased expression of chemokines, cytokines and antigen-presenting molecules, and enhanced microbial killing. Based on our overarching hypothesis that polarization-associated cell states are important determinants of macrophage function during immune and inflammatory responses, in the previous project period we investigated chromatin-based epigenetic mechanisms and changes in metabolism induced by IFN-? during M1 polarization of human macrophages, and how this affects inflammatory TLR-induced responses. We found that IFN-? globally reprograms the epigenetic landscape of macrophages by inducing stable STAT1 binding and changes in histone marks. IFN-?-induced chromatin remodeling cooperated with TLR signaling to synergistically activate inflammatory genes. We found a new link between epigenetics and metabolism, as IFN-? epigenetically silenced components of M2 alternative activation that included the master metabolic regulator PPAR?. IFN-? also altered macrophage metabolism by targeting mTORC1, which senses and coordinates cellular responses to the nutrient status of extracellular and intracellular microenvironments. Suppression of mTORC1 was associated with selective regulation of protein translation, autophagy, and skewing of inflammatory cytokine production. In this project, we will investigate mechanisms and functional consequences of epigenetic and metabolic regulation of human macrophage polarization by IFN-?, and how this alters macrophages to increase inflammatory activation and anti-microbial functions. We anticipate our studies will yield insights that can be used to develop therapies to modulate macrophage function in innate immune responses and inflammatory diseases.