Establishing an immune mechanome

ABSTRACT Mechanical forces are often modulated in diseased or wounded tissues as a result of inflammatory responses driven by immune cell activity in the affected site(s). In fact, aberrant mechanical force generation in pathological settings may mediate disease progression and treatment resistance. However, little is known about the response of immune cells to these mechanical forces, particularly at the tissue-length scale, and even in normal physiological settings. Thus there is a critically unmet need to fill overlooked gaps in our basic understanding of the interplay between tissue-level mechanical forces and immune cell behavior, both collectively and at the single-cell level. With the support of the NIGMS R35 MIRA for Early Stage Investigators over the next five years, my laboratory will establish the first immune mechanome. We will investigate the impact of tissue mechanical forces on the phenotype and function of innate and adaptive immune cells in a variety of organs. Leveraging engineering-based tools and approaches, we will couple unbiased omics platforms to mechanical testing at multiple scales (e.g., on cells in vivo, tissues ex vivo, and organs in vivo) in order to relate immune response to mechanical forces. During multiscale compression, the trafficking, distribution, motility, cell-cell interactions, and functional behavior of immune cells will be examined and perturbed via: i) intravital and dynamic imaging (e.g., with multiphoton microscopy of fluorescent cells or genetically engineered mouse models); ii) immunocompetent, transgenic, and immunogenic animal models (e.g., OT-I/OT-II antigen systems); and iii) artificial intelligence- based cell state analysis (e.g., from single cell RNA sequencing). We will also explore our hypothesis that beneficial immune activity in the face of pathological conditions is suppressed by heightened tissue mechanical forces. Importantly, the proposed Projects are to be performed in non-specific contexts that are independent of tissue type, organ, or disease in order to maximize the potential for broad impact in the biomedical sciences. The knowledge generated will lay the groundwork for future mechanistic and translational research in both healthy and diseased settings. By operating at the interface of mechanical engineering and immunology in the burgeoning field of “mechano-immunology,” my research program is uniquely suited to reveal new biophysical insights and pathophysiological targets for human disease.