Heme Oxygenase-1 Induction by Blood-Feeding Arthropods Controls Skin Inflammation and Promotes Disease Tolerance
Thiago DeSouza‐Vieira, Eva Iniguez, Tiago D. Serafim, Waldionê de Castro, Subir Karmakar, Maria M. Disotuar, Pedro Cecílio, Joshua R. Lacsina, Claudio Meneses, Bianca M. Nagata, Sílvia Cardoso, Daniel E. Sonenshine, Ian N. Moore, Valéria M. Borges, Ranadhir Dey, Miguel P. Soares, Hira L. Nakhasi, Fabiano Oliveira, Jesús G. Valenzuela, Shaden Kamhawi
Abstract
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 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 disease tolerance to vector-borne pathogens.