IL1R1-Mediated Trained Emergency Myelopoiesis Maximizes Hematopoietic Fitness in Recurrent and Sustained Infections

Abstract

Emergency myelopoiesis (EM) represents a general hematopoietic response to infection, but how infection frequency and duration are sensed is unknown. Here we describe a IL1R1-mediated trained hematopoietic response program, termed trained emergency myelopoiesis (TEM), in recurring E.coli infection and sustained C. albicans infection. IL1R1 upregulation, triggered by primary infection via TLR2 in specific BM hematopoietic stem and progenitor cells, formed an intrinsic and transplantable short-lived hematological memory that contributed to specific IL-1 signaling upregulation and reinforced myelopoiesis in sustained and instantly-recurring infection. IL1R1 disruption impaired TEM and neutrophil recovery, diminished microbicidal capability, and increased mortality in hosts subjected to sustained C. albicans infection or re-infected with E.coli before neutrophil restoration, while vaccination with heat-inactivated E.coli or a TLR2 agonist significantly accelerated IL1R1-dependent myelopoiesis and BM recovery in irradiated hosts. Importantly, IL-1 signaling was not significantly augmented during naïve EM and IL1R1 disruption did not affect rapid EM elicited by a single infection. Collectively, IL1R1-mediated reprogramming and training of the hematopoietic machinery adapt myelopoiesis to infection frequency and duration.

Keywords: Hematological memory, Innate Immunity, interleukin-1 receptor, Hematopoiesis, myelopoiesis, Recurrent or sustained infection