Microenvironment, condesates and control of inflammation

Inflammatory response is essential for defending tissue and organ integrity. When hosts encounter challenge of tissue homeostasis, such as infections or injuries, an inflammatory response is activated by the innate sensors recognizing cues associated with pathogens or tissue damage. These inflammatory triggers activate production of cytokines, chemokines and additional immune signals to mount host defense and tissue repair programs. A proper and successful inflammatory response restore tissue homeostasis. However, in excessive, inflammatory responses are known causes for significant tissue damage. Much of our knowledge in inflammation relates to the initiation of inflammatory responses and the impact on organs functions. By contrast, little is known of how state of a given tissue impacts the inflammatory response. We hypothesize that sensing deviation in tissue microenvironment by the immune system may provide such balancing mechanism.

My lab uses an interdisciplinary, systems and immunology approach, focused on immune-stromal interactions and Immune-environment interactions. We are interested in discovering novel strategies for immune systems to sense, respond to and adapt to perturbation in the chemical environment, and design syntenic modules to control environment-dependent immunity. We recently found that macrophages, a type of innate immune cell type defending our body against microbial infections, sense tissue acidification to adjust inflammatory responses. We identified mammalian BRD4 as a novel intracellular pH sensor. Acidic pH disrupts the transcription condensates containing BRD4 and MED1, via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.