Heme Oxygenase-1 Induction by Blood Feeding Arthropods Controls Skin Inflammation and Promotes Tolerance to Pathogens

Hematophagous vectors lacerate host skin and capillaries to acquire a blood meal resulting in leakage of red blood cells (RBCs) and inflammation. Here, we show that heme oxygenase-1 (HO-1), a pleiotropic cytoprotective isoenzyme that mitigates heme-mediated tissue damage, is induced after bites of sand flies, mosquitoes and ticks. Further, we demonstrate that erythrophagocytosis by macrophages, including a skin-residing CD163+CD91+ professional iron recycling subpopulation, produces HO-1 after insect bites. Importantly, we establish that global deletion or transient inhibition of HO-1 in mice increases inflammation and pathology following Leishmania-infected sand fly bites without affecting parasite number; whereas CO, an end-product of the HO-1 enzymatic reaction suppresses skin inflammation. This indicates that HO-1 induction by blood feeding sand flies promotes tolerance to Leishmania infection. Collectively, our data demonstrate that HO-1 induction through erythrophagocytosis is a universal mechanism that regulates skin inflammation following blood feeding by arthropods thus promoting early-stage tolerance to vector-borne pathogens.