Cell Size Inheritance and Innate Immune Memory

About This Grant

Project Summary Excessive cell growth contributes to senescence and is a hallmark of aging. In the innate immune system, monocyte distribution width (the standard deviation of the monocyte mean volume) has been proposed as a diagnostic marker for severe infection and early sepsis detection. Increased cell size is also associated with an exhaustion-like memory state. While both senescence and immune exhaustion can be pathogenic, they differ in their reversibility: senescence is characterized by an irreversible cell cycle arrest, whereas exhaustion in innate immune cells retains cell cycle activity and proliferative potential. It remains unclear how enlarged immune cells in an exhausted state can maintain immune surveillance without transitioning into senescence. Our unpublished work identifies a pathway regulated by the endocytic protein FBP17 that increases the cell size setpoint without inducing senescence. FBP17-deficient mast cells and macrophages remain proliferative despite their enlarged size. Similarly, exhausted monocytes subjected to repeated LPS stimulation in vitro exhibit both increased cell size and reduced FBP17 expression. In vivo, we also made a novel observation that monocytes isolated from aged mice with exhaustion-like memory signatures display reduced levels of FBP17, which strongly correlate with their enlarged size compared to monocytes from young mice. These findings suggest that cell enlargement does not inherently lead to proliferative arrest and that increases in cell size may be reversible. Using a single-cell microchannel system to monitor real-time cell growth and quantify size homeostasis, we further discovered that FBP17 knockdown cells increase their sizes through an "adder" growth mechanism. In this model, cells do not divide upon reaching a specific size threshold; instead, they add a fixed volume each generation. This behavior implies a form of transgenerational memory that depends on lineage age. We hypothesize that FBP17, along with the adder-based enlargement mechanism, plays a key role in enabling immune cells to grow without entering senescence. We aim to investigate how size increment is regulated via growth rate modulation, the molecular basis of intergenerational memory transmission, and whether this mechanism contributes to immune exhaustion memory. Understanding this non-canonical pathway of cell size regulation will offer novel strategies for reversing aging-associated cellular changes.