Tissue-Resident CCR2+ Macrophage TREM-1/3 Signaling is Necessary for Leukocyte Recruitment to Injured Hearts

The triggering receptor expressed on myeloid cells-1 (TREM-1) has been shown to amplify inflammatory signals, such as Toll-like receptor signaling, after infections and after sterile injury. While previous studies have demonstrated that TREM-1 activation on circulating immune cells promotes injury, the role of TREM-1 signaling in tissue-resident cells in the propagation of sterile inflammation remains poorly understood. Here, we took advantage of a cardiac transplantation model to dissect how TREM-1/3 expression on heart-resident cells regulates sterile inflammation. Using single cell RNA sequencing, intravital microscopy and positron emission tomography (PET)-based imaging we discovered that TREM-1/3 signaling in donor tissue-resident CCR2+ macrophages promotes CCL3 production and is critical for the recruitment of neutrophils and CCR2+ monocytes early after reperfusion. We demonstrate prolonged allograft survival in TREM-1/3-deficient compared with wildtype hearts. Thus, we identify TREM-1/3 signaling in donor grafts as a potential future therapeutic target to diminish inflammation after heart transplantation.