6533b86efe1ef96bd12cb614

RESEARCH PRODUCT

Notch and TLR signaling coordinate monocyte cell fate and inflammation

Jaba GamrekelashviliTim SparwasserAndre SitnowPhilip WenzelKhaled DastagirMatthias LochnerBernhard HolzmannHermann HallerCorina RatiuUlrich KalinkeTamar KapanadzeSusanne KarbachStefan SablotnySusanne FleigFlorian P. Limbourg

subject

0301 basic medicineMouseQH301-705.5ScienceNotch signaling pathwayInflammationSpleenBiologyCell fate determinationSystemic inflammationGeneral Biochemistry Genetics and Molecular BiologyMonocytesimmunology03 medical and health sciencesMice0302 clinical medicineImmunology and InflammationmedicineAnimalsReceptor Notch2Biology (General)Receptormousemacrophage differentiationInflammationMembrane GlycoproteinsGeneral Immunology and MicrobiologyGeneral NeuroscienceMonocyteQRCell DifferentiationTLR signalingGeneral MedicineTLR7notch signalingCell biology030104 developmental biologymedicine.anatomical_structureToll-Like Receptor 7inflammationmonocytes and macrophagesMedicinemedicine.symptom030215 immunologySignal TransductionResearch Article

description

AbstractConventional Ly6Chi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6Chi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6Clo monocyte development. At the same time, TLR7 stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes and ectopic differentiation of Ly6Chi monocytes into macrophages and dendritic cells, which appear in the blood stream and infiltrate the spleen and major blood vessels, resulting in unrestrained systemic inflammation. Thus, Notch2 is a master regulator of Ly6Chi monocyte cell fate and inflammation in response to TLR signaling.

yearjournalcountryeditionlanguage
2020-05-01
10.1101/2020.04.28.066217http://dx.doi.org/10.1101/2020.04.28.066217