APOE Protects Against Severe Infection with Mycobacterium tuberculosis by Restraining Production of Neutrophil Extracellular Traps

Mice lacking apolipoprotein E (APOE, Apoe-/- mice) are highly susceptible to infection with Mycobacterium tuberculosis (Mtb) but the underlying immune dysregulation has been unclear. We found that Mtb infected Apoe-/- mice have significantly elevated levels of neutrophils in their lungs compared to controls and demonstrated that depleting neutrophils, depleting pDCs, blocking type1 interferon signaling, and blocking LTB4 receptor signaling all improved the outcome of Mtb-infected Apoe-/- mice. Neutrophils can undergo a specialized form of cell death termed NETosis in which activation of the enzyme PAD4 leads to extrusion of neutrophil extracellular traps (NETs). NETs have been associated with severe tuberculosis in other mouse models and in humans but a role of NETs in the pathology has not been directly established. We demonstrate that blocking PAD4 activation leads to a decrease in NETs in the lungs and, strikingly, completely reverses the hypersusceptiblity of Apoe-/- mice.