CELL-REPORTS-D-20-01909_De Souza-Vieira, Iniguez et al., 2020. Raw Data

Heme oxygenase-1 induction by blood feeding arthropods controls skin inflammation and promotes disease tolerance. 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 disease tolerance to vector-borne pathogens.吸血节肢动物诱导的血红素加氧酶-1（heme oxygenase-1）可调控皮肤炎症并促进疾病耐受。 吸血媒介会撕裂宿主皮肤与毛细血管以取食血液，进而导致红细胞（red blood cells, RBCs）漏出并引发炎症。本研究发现，白蛉、蚊虫与蜱虫叮咬后，可诱导血红素加氧酶-1（heme oxygenase-1, HO-1）的表达——该酶是一类可减轻血红素介导的组织损伤的多效性细胞保护性同工酶。 进一步研究证实，昆虫叮咬后，巨噬细胞（包括驻留皮肤的CD163+CD91+专职铁回收亚群）的红细胞吞噬作用可诱导HO-1产生。 尤为重要的是，本研究证实，在小鼠体内对HO-1进行全基因敲除或瞬时抑制，会增加利什曼原虫感染的白蛉叮咬后的炎症反应与病理损伤，但不会影响寄生虫数量；而HO-1酶促反应的终产物一氧化碳（carbon monoxide, CO）可抑制皮肤炎症。这表明吸血白蛉诱导的HO-1表达可促进机体对利什曼原虫感染的耐受。 综上，本研究数据证实，通过红细胞吞噬作用诱导HO-1表达，是节肢动物吸血后调控皮肤炎症的通用机制，进而可促进机体对虫媒病原体产生早期疾病耐受。