Supplementary Material for: IL-37 Causes Excessive Inflammation and Tissue Damage in Murine Pneumococcal Pneumonia

Streptococcus pneumoniae infections can lead to severe
complications with excessive immune activation and tissue damage.
Interleukin-37 (IL-37) has gained importance as a suppressor of innate
and acquired immunity, and its effects have been therapeutic as they
prevent tissue damage in autoimmune and inflammatory diseases. By using
RAW macrophages, stably transfected with human IL-37, we showed a 70%
decrease in the cytokine levels of IL-6, TNF-α, and IL-1β, and a
2.2-fold reduction of the intracellular killing capacity of internalized
pneumococci in response to pneumococcal infection. In a murine model of
infection with S. pneumoniae, using mice transgenic for human
IL-37b (IL-37tg), we observed an initial decrease in cytokine expression
of IL-6, TNF-α, and IL-1β in the lungs, followed by a late-phase
enhancement of pneumococcal burden and subsequent increase of
proinflammatory cytokine levels. Additionally, a marked increase in
recruitment of alveolar macrophages and neutrophils was noted, while
TRAIL mRNA was reduced 3-fold in lungs of IL-37tg mice, resulting in
necrotizing pneumonia with augmented death of infiltrating neutrophils,
enhanced bacteremic spread, and increased mortality. In conclusion, we
have identified that IL-37 modulates several core components of a
successful inflammatory response to pneumococcal pneumonia, which lead
to increased inflammation, tissue damage, and mortality.

肺炎链球菌（Streptococcus pneumoniae）感染可引发伴随过度免疫激活与组织损伤的严重并发症。白细胞介素-37（Interleukin-37，IL-37）作为固有免疫与适应性免疫的负调控因子受到广泛关注，其可通过抑制免疫活化预防自身免疫性及炎症性疾病中的组织损伤，展现出治疗潜力。本研究通过稳定转染人IL-37的RAW巨噬细胞开展实验，结果显示：IL-6、TNF-α及IL-1β的细胞因子水平下降70%，而在肺炎链球菌感染刺激下，被巨噬细胞吞噬的肺炎链球菌的胞内杀伤能力降低至原水平的1/2.2。在转人IL-37b基因的转基因小鼠（IL-37tg）肺炎链球菌感染模型中，我们观察到小鼠肺部IL-6、TNF-α及IL-1β的细胞因子表达水平最初出现下降，但随后肺炎链球菌负荷在感染晚期出现升高，促炎细胞因子水平亦随之上升。此外，研究还发现肺泡巨噬细胞与中性粒细胞的招募显著增加；同时IL-37tg小鼠肺部的肿瘤坏死因子相关凋亡诱导配体（TRAIL）mRNA表达水平下调3倍，最终引发坏死性肺炎，表现为浸润性中性粒细胞死亡增多、菌血症播散加剧以及死亡率升高。综上，本研究证实IL-37可调控针对肺炎链球菌肺炎的有效炎症应答的多个核心环节，最终导致炎症加重、组织损伤加剧与死亡率升高。