Interferon-Tau Attenuates Uptake of Nanoparticles and Secretion of Interleukin-1β in Macrophages

Background
Type I interferons (IFNs), including IFN-alpha (IFNA) and IFN-beta (IFNB), have anti-inflammatory properties and are used to treat patients with autoimmune and inflammatory disorders. However, little is known of the role of IFN-tau (IFNT), a type I IFN produced by ruminant animals for inflammation. Because IFNB has recently been shown to inhibit nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome activation and subsequent secretion of the potent inflammatory cytokine interleukin (IL)-1β, we examined the effects of ruminant IFNT on NLRP3 inflammasome-mediated IL-1β secretion in human THP-1 macrophages.
Methods and Results
IFNT dose-dependently inhibited IL-1β secretion induced by nano-silica, a well-known activators of NLRP3 inflammasomes, in human macrophages primed with lipopolysaccharide (LPS, TLR4 agonist) and Pam3CSK4 (TLR1/2 agonist). IFNT also suppressed phagocytosis of nano-silica and reactive oxygen species (ROS) generation. Western blot analysis showed that IFNT inhibited both pro-IL-1β and mature IL-1β. In addition, real-time RT-PCR analysis showed that IFNT suppressed IL-1β mRNA expression induced by LPS and Pam3CSK4. Although nano-silica particles did not induce IL-10 secretion, IFNT induced IL-10 secretion in a dose-dependent manner. Furthermore, IFNT-suppressed IL-1β secretion was restored by anti-IL-10 neutralizing antibody.
Conclusions
Ruminant IFNT inhibits NLRP3 inflammasome-driven IL-1β secretion in human macrophages via multiple pathways, including the uptake of nano-silica particles, generation of ROS, and IL-10-mediated inhibition of pro-IL-1β induction. It may be a therapeutic alternative to IFNA and IFNB.

研究背景
I型干扰素（Type I interferons, IFNs）包含α干扰素（IFN-α, IFNA）与β干扰素（IFN-β, IFNB），具备抗炎活性，目前被用于治疗自身免疫性疾病与炎症性疾病患者。然而，目前对于τ干扰素（IFN-τ, IFNT）——一种由反刍动物产生的I型干扰素——在炎症中的作用仍不甚明确。鉴于近期研究证实IFN-β可抑制核苷酸结合寡聚化结构域样受体蛋白3（nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3, NLRP3）炎症小体的激活，以及强效促炎细胞因子白细胞介素（interleukin, IL）-1β的后续分泌，本研究探究了反刍动物来源的IFNT对经脂多糖（lipopolysaccharide, LPS，TLR4激动剂）与Pam3CSK4（TLR1/2激动剂）预刺激的人源THP-1巨噬细胞中，NLRP3炎症小体介导的IL-1β分泌的影响。

研究方法与结果
IFNT可剂量依赖性地抑制纳米二氧化硅诱导的IL-1β分泌——纳米二氧化硅是一类经典的NLRP3炎症小体激活剂——在经LPS与Pam3CSK4预刺激的人源巨噬细胞中。IFNT同时可抑制纳米二氧化硅的吞噬作用与活性氧（reactive oxygen species, ROS）的产生。蛋白质印迹（Western Blot）分析结果显示，IFNT可同时抑制前体IL-1β与成熟IL-1β的表达。此外，实时定量逆转录聚合酶链反应（real-time RT-PCR）分析表明，IFNT可抑制LPS与Pam3CSK4诱导的IL-1β mRNA表达。尽管纳米二氧化硅颗粒未诱导白细胞介素（interleukin, IL）-10的分泌，但IFNT可剂量依赖性地诱导IL-10的分泌。进一步研究发现，抗IL-10中和抗体可逆转IFNT对IL-1β分泌的抑制作用。

研究结论
反刍动物来源的IFNT可通过多条通路抑制人源THP-1巨噬细胞中NLRP3炎症小体介导的IL-1β分泌，包括纳米二氧化硅颗粒的摄取、活性氧的产生，以及IL-10介导的前体IL-1β诱导抑制。其有望成为IFN-α与IFN-β的替代治疗方案。