Macrophage population diversity as a determinant of primary and secondary responses to LPS

Tissue-resident macrophages are the first responder cells of the immune system that phagocytose, present antigens and promote inflammation by secreting soluble factors (cytokines, chemokines, nitric oxide, etc) that act in an autocrine and paracrine manner. This response has been
shown to be heterogeneous at mRNA level in single cells suggesting not all macrophages ‘fire’ an equal response. Such heterogeneity can have implications on how inflammation is established or modulated when there is a pathogenic invasion locally such as in wounds or systemically, as in the case of severe blood infections.
Here, we ask how single and repeated challenge with LPS affects heterogeneity of macrophage communities. Through combining empirical measurements of inflammatory
proteins such as TNF, IL-6, NOS2, and IL-1β Pro at the single-cell level with mathematical simulations, we show distinct heterogenous communities of macrophages emerge following primary and secondary LPS challenges.
Furthermore, we show that restricting inter-cellular communication or impairing microRNA-mediated silencing, a key cellular process thought to determine population heterogeneity, affect the composition of macrophage communities and responses to LPS. Overall, our results demonstrate that macrophage communities of diverse micro-composition can demonstrate similar macroscopic cytokine responses indicating that population-level robustness and plasticity underpin innate immunity to LPS.