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

• Published in: Cell reports (Cambridge) Vol. 33; no. 4; p. 108317
• Main Authors: DeSouza-Vieira, Thiago, Iniguez, Eva, Serafim, Tiago D., de Castro, Waldionê, Karmakar, Subir, Disotuar, Maria M., Cecilio, Pedro, Lacsina, Joshua R., Meneses, Claudio, Nagata, Bianca M., Cardoso, Silvia, Sonenshine, Daniel E., Moore, Ian N., Borges, Valeria M., Dey, Ranadhir, Soares, Miguel P., Nakhasi, Hira L., Oliveira, Fabiano, Valenzuela, Jesus G., Kamhawi, Shaden
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.10.2020
• Subjects: disease tolerance; erythrophagocytosis; hematophagous arthropods; heme oxygenase-1; inflammation; Leishmania; mosquitoes and ticks; red blood cells; sand fly; vector-borne disease; red blood cells; inflammation; Leishmania; disease tolerance; mosquitoes and ticks; hematophagous arthropods; erythrophagocytosis; heme oxygenase-1; vector-borne disease; sand fly
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108317

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. [Display omitted] •Blood-feeding arthropod bites damage blood vessels, causing RBC leakage into tissue•Extravascular RBCs are ingested by skin macrophages, leading to production of HO-1•Inhibition of HO-1 enhances inflammation and promotes tissue damage•HO-1 production after Leishmania-infected sand fly bites promotes disease tolerance Vector-borne diseases afflict millions of people worldwide. DeSouza-Vieira et al. demonstrate that blood-feeding arthropods induce HO-1 in skin macrophages that ingest extravascular erythrocytes from damaged vessels. Without HO-1, sand fly transmission of Leishmania led to aggravated cutaneous leishmaniasis pathology without affecting the parasites, indicating that HO-1 production promotes disease tolerance.