Title : Innate Immune memory based therapeutics in the resolution of inflammation
Abstract:
Emerging studies suggest a novel role of innate immune memory during the pathogenesis and treatment of diverse inflammatory diseases. However, the fundamental principles that underlie the generation of innate immune memory are not well understood, thus hindering the effective development of innate-based therapeutics. We have defined the signal-strength and history dependent memory adaptation of innate immune cells including monocytes and neutrophils in both murine and human systems. Integrative single cell RNAseq and protein-based analyses reveal the existence of unique subsets of memory monocytes/neutrophils with divergent inflammatory and/or resolving natures. Genetic studies reveal that TRAM-mediated signaling circuitry is required for the establishment of inflammatory and/or exhausted innate memory leukocytes, and that the deletion of TRAM can effectively reprogram innate immune cells into a novel resolving phenotype. Our pharmacological approach independently reveal that the application of 4-PBA can similarly reprogram resolving innate immune cells conducive for the treatment of both acute sepsis as well as chronic inflammatory atherosclerosis. Taken together, our systems analyses reveal that resolving innate leukocytes have therapeutic potentials in restraining inflammation and promoting host defense.
