Severe infection constitutively upregulates TIMP1 in the bone marrow hematopoietic niche to support long-term enhanced myelopoiesis

Infection is able to elicit innate immunological memory by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. The infection experience is imprinted in the bone marrow (BM) stromal cells, in the form of a constitutive upregulation of the tissue inhibitor of metalloproteinases 1 (TIMP1). TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of Notch which in turn suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis post infection. Thus, our data reveal that infection could establish an inflammatory memory in the BM niche to support a long-term enhanced output of innate immune cells. Overall design: Adult C57BL/6 mice were subjected to sham or cecal ligation and puncture (CLP) surgery. At week 12 after surgery, lineage marker-negative Kit+ Sca1+ (LSK) hematopoietic stem and progenitor cells were sorted for scRNA-seq.