Macrophages have remarkable plasticity and are able to respond and polarize to both chemical and biophsyical changes in their microenvironment.  Changes at the transcriptional level dictate whether macrophages will take on inflammatory or anti-inflammatory phenotypes. We have previously shown the role of the mechanosensitive transcription factor YAP on regulation of inflammatory activity in macrophages.

Using different genetic macrophage constructs of YAP as well as techniques such as RNA-seq and high resolution microscopy, we are currently unraveling, at the transcriptional level, the role of mechanosensation on macrophage fusion (a common phenomena seen with implanted materials), metabolism, and inflammatory polarization.  We are also investigating how Piezo1 mechanotransduction is linked to YAP activity and epigenetic reprogramming.  Our long-term goal is to control the host immune response to implanted biomaterials, and thus achieve integrated function of medical devices and tissue engineered constructs.

While each tissue has a physiological modulus, several diseases are characterized by a stiffening of microenvironments within these tissues.  The Piezo1 ion channel is a mechanoreceptor crucial for many functions including immune sensation and response to changing biophysical cues.  Using a mouse model of atherosclerosis, we have shown marked upregulation of Piezo1 expression within the stiff plaques that appear only in the diseased aorta.  

We are further exploring the overall role of Piezo1 in atherogenesis and alterations to key lipid homeostasis markers in macrophages that contribute to plaque formation. We are also elucidating the role of Piezo1 on metabolic regulation of both mouse and human  microglia in Alzheimer’s disease. Because metabolism is a key regulator in switching immune phenotype, here we are researching functional lipid metabolic responses to Piezo1 activation/knockdown and the downstream effects on microglia functions that are detrimental in AD.

Our lab designs novel technologies to modulate the innate immune response and microfabricated biomaterials to study immune function.  We have recently developed and shown how apoptotic neutrophils laden hydrogels can aid in the wound healing process through alternative activation of local macrophages which we are exploring further applications.  In the brain we are investigating the use of nanoparticles CD200 conjugated microparticles in attenuating neuroinflammation by modulating activation of the brain’s resident immune cell – microglia – a key feature in aging that makes the brain vulnerable to neurodegeneration.  We’ve additionally leveraged organ-on-a-chip technology to help develop an immune-cardiac chip allowing us to monitor features of the immune response to conditions such hypoxia on heart tissue.