Department of Microbiology & Immunology, Weill Cornell Medicine, New York, NY, 10065, USA.
Immunology & Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, 10065, USA.
EMBO Rep. 2024 Jul;25(7):3064-3089. doi: 10.1038/s44319-024-00171-0. Epub 2024 Jun 12.
Type I interferons (IFN-I) are implicated in exacerbation of tuberculosis (TB), but the mechanisms are unclear. Mouse macrophages infected with Mycobacterium tuberculosis (Mtb) produce IFN-I, which contributes to their death. Here we investigate whether the same is true for human monocyte-derived macrophages (MDM). MDM prepared by a conventional method markedly upregulate interferon-stimulated genes (ISGs) upon Mtb infection, while MDM prepared to better restrict Mtb do so much less. A mixture of antibodies inhibiting IFN-I signaling prevents ISG induction. Surprisingly, secreted IFN-I are undetectable until nearly two days after ISG induction. These same antibodies do not diminish Mtb-infected MDM death. MDM induce ISGs in response to picogram/mL levels of exogenous IFN-I while depleting similar quantities from the medium. Exogenous IFN-I increase the proportion of dead MDM. We speculate that Mtb-infected MDM produce and respond to minute levels of IFN-I, and that only some of the resultant signaling is susceptible to neutralizing antibodies. Many types of cells may secrete IFN-I in patients with TB, where IFN-I is likely to promote the death of infected macrophages.
I 型干扰素（IFN-I）与结核病（TB）恶化有关，但具体机制尚不清楚。感染结核分枝杆菌（Mtb）的小鼠巨噬细胞会产生 IFN-I，这有助于其死亡。在这里，我们研究了人类单核细胞衍生的巨噬细胞（MDM）是否也是如此。通过常规方法制备的 MDM 在感染 Mtb 后会明显上调干扰素刺激基因（ISGs），而制备时更好地限制 Mtb 的 MDM 则不会。抑制 IFN-I 信号的抗体混合物可防止 ISG 诱导。令人惊讶的是，分泌型 IFN-I 在诱导 ISG 后近两天才检测到。这些相同的抗体不会减少感染 Mtb 的 MDM 死亡。MDM 会对外源 IFN-I 的皮克/毫升水平做出反应，从而诱导 ISGs，同时从中性化培养基中去除相似数量的 IFN-I。外源性 IFN-I 增加了死亡 MDM 的比例。我们推测，感染 Mtb 的 MDM 会产生并对微量的 IFN-I 做出反应，并且只有部分信号易受中和抗体的影响。在结核病患者中，许多类型的细胞可能会分泌 IFN-I，而 IFN-I 可能会促进感染的巨噬细胞死亡。
