Non-cell autonomous innate immune memory from positive feedback

Innate immune response to acute inflammatory challenges includes epigenetic changes in myeloid cells such as tissue macrophages and monocytes, as well as in cells of the hematopoietic hierarchy in the bone marrow. These epigenetic changes have been hypothesized to give rise to long-lasting innate immune memory termed trained immunity. However, the kinetics of such epigenetic activation remain uncharacterized. Here, we first use mathematical models of tissue macrophage dynamics and of the monocyte-generating hematopoietic process to show that the duration for which trained immunity can last is strictly limited by the fidelity with which epigenetic information is transmitted during cell division and differentiation, in addition to the cell lifespan. We then show that the presence of cytokine signaling-mediated positive feedback to the epigenetic state of hematopoietic or effector myeloid cells is sufficient to establish trained immunity that can last far longer than the lifespan of individual cells, even when epigenetic information is lost during cell division and differentiation. Simulating the model dynamics for an ensemble of randomly sampled parameter sets and analyzing the outcome using a random forest-based approach, we identified feedback strength as the key determinant of memory duration. Overall, we describe a plausible non-cell autonomous mechanism for long-lasting innate immune memory.