Tian Tian, Jin Michelle Qiushuang, Dubin Krista, King Sandra L, Hoetzenecker Wolfram, Murphy George F, Chen Chen Amy, Kupper Thomas S, Fuhlbrigge Robert C
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
Stanford University, Stanford, CA 94305.
J Immunol. 2017 Jun 1;198(11):4341-4351. doi: 10.4049/jimmunol.1500106. Epub 2017 May 3.
The IL-1 superfamily of cytokines and receptors has been studied extensively. However, the specific roles of IL-1 elements in host immunity to cutaneous viral infection remain elusive. In this study, we applied vaccinia virus (VACV) by scarification to IL-1R1 knockout mice (IL-1R1) and found that these mice developed markedly larger lesions with higher viral genome copies in skin than did wild-type mice. The phenotype of infected IL-1R1 mice was similar to eczema vaccinatum, a severe side effect of VACV vaccination that may develop in humans with atopic dermatitis. Interestingly, the impaired cutaneous response of IL-1R1 mice did not reflect a systemic immune deficiency, because immunized IL-1R1 mice survived subsequent lethal VACV intranasal challenge, or defects of T cell activation or T cell homing to the site of inoculation. Histologic evaluation revealed that VACV infection and replication after scarification were limited to the epidermal layer of wild-type mice, whereas lack of IL-1R1 permitted extension of VACV infection into dermal layers of the skin. We explored the etiology of this discrepancy and determined that IL-1R1 mice contained significantly more macrophages and monocyte-derived dendritic cells in the dermis after VACV scarification. These cells were vulnerable to VACV infection and may augment the transmission of virus to adjacent skin, thus leading to larger skin lesions and satellite lesions in IL-1R1 mice. These results suggest new therapeutic strategies for treatment of eczema vaccinatum and inform assessment of risks in patients receiving IL-1 blocking Abs for treatment of chronic inflammatory disorders.
细胞因子和受体的白细胞介素-1（IL-1）超家族已得到广泛研究。然而，IL-1元件在宿主对皮肤病毒感染的免疫中的具体作用仍不清楚。在本研究中，我们通过划痕接种法将痘苗病毒（VACV）应用于IL-1R1基因敲除小鼠（IL-1R1−/−），发现这些小鼠皮肤中的损伤明显更大，病毒基因组拷贝数也高于野生型小鼠。感染的IL-1R1−/−小鼠的表型类似于种痘后湿疹，这是VACV疫苗接种的一种严重副作用，可能在患有特应性皮炎的人类中发生。有趣的是，IL-1R1−/−小鼠受损的皮肤反应并不反映全身免疫缺陷，因为免疫后的IL-1R1−/−小鼠在随后的致死性VACV鼻内攻击中存活下来，也不存在T细胞激活缺陷或T细胞归巢到接种部位的缺陷。组织学评估显示，划痕接种后VACV在野生型小鼠中的感染和复制仅限于表皮层，而缺乏IL-1R1则使VACV感染扩展到皮肤的真皮层。我们探究了这种差异的病因，确定在VACV划痕接种后，IL-1R1−/−小鼠的真皮中含有明显更多的巨噬细胞和单核细胞衍生的树突状细胞。这些细胞易受VACV感染，可能会增加病毒向相邻皮肤的传播，从而导致IL-1R1−/−小鼠出现更大的皮肤损伤和卫星状损伤。这些结果为种痘后湿疹的治疗提出了新的治疗策略，并为评估接受IL-1阻断抗体治疗慢性炎症性疾病的患者的风险提供了参考。
