Inflammation is essential in the early stages of battling an invading pathogen, but can become damaging to the host if not resolved in a timely manner. Indeed, prolonged and unresolved inflammation is responsible for the hospitalizations and deaths of many COVID-19 patients. An excess of circulating pro-inflammatory cytokines is one feature of severe COVID-19, and now Koenis and colleagues show that certain pro-resolving factors are out of balance in such patients too. While blood samples from patients with mild COVID-19 revealed an increase in specialized pro-resolving lipid mediators (SPMs), those from patients with severe disease had lower levels of these lipid factors. Expression of SPM receptors on phagocytes was also higher in patients with mild disease than those with severe COVID-19. And, in line with this, the proportion of activated pro-inflammtory phagocytes was higher in patients with severe disease. The team went on to show that patients treated with the steroid dexamethasone had increased blood levels of SPMs. Together the results reveal SPMs are dysregulated in severe cases of COVID-19 and suggest SPM modulation, whether via steroid administration or other pharmacological means, could promote resolution of out-of-control inflammation.

Several genome-wide association studies (GWAS) have identified variants at the ADAMTS7 gene and its surrounding intergenic regions as risk loci for coronary artery disease. Furthermore, animal studies suggest the ADAMTS7 protein, which is both a metalloproteinase enzyme and a proteoglycan, is pro-atherogenic. However, which of the protein’s identities is responsible for promoting atherosclerosis is unclear. Mizoguchi and colleagues now show that the enzymatic function of ADAMTS7 is to blame. The team generated mice with [a] catalytically inactive version of ADAMTS7 and compared these animals with ones that either lacked ADAMTS7 entirely or had the fully intact protein (wild type). They found that loss of either ADAMTS7 protein itself or just its catalytic function was enough to reduce plaque burden in two different models of atherosclerosis. ADAMTS7 is known to regulate migration of vascular smooth muscle cells (VSMCs), which contributes to plaque formation, and VSMCs lacking either the full protein or just its catalytic activity had impaired migratory activity, the team showed. Together the results pinpoint ADAMTS7’s enzyme activity as pro-atherogenic and suggest the catalytic domain of the protein could be a therapeutic target for curtailing atherosclerosis.

The developing heart is thought to originate from two populations of cells—the first and second heart fields—which are first identifiable in the stage E7.5 mouse embryo (day 15 human embryo). Genes controlling the development of these fields have been linked to congenital heart defects (CHDs), but interestingly CHDs are also sometimes linked to placental abnormalities for reasons that are unclear. Zhang and colleagues now show that the first heart field and extraembryonic tissues—those which gives rise to the yolk sac and placenta—have an unexpected link. Through lineage-tracing experiments and single-cell transcriptomics, the team discovered that the first heart field consists of two sources of mesoderm progenitors—one that is embryonic in nature, and the other that arises from the interface between extraembryonic and embryonic tissues of the early gastrula. This latter population of progenitors, which expresses the transcription factor Hand1, gives rise to extraembryonic mesoderm cells in addition to heart field cells, the team showed. The finding of this shared source of mesodermal progenitors not only blurs the lines between the embryo and its supporting tissues, but may also explain the link between placental abnormalities and CHDs.

在与入侵病原体作斗争的早期阶段，炎症是必不可少的，但如果不及时解决，就会对宿主造成损害。事实上，长期和未解决的炎症是许多 COVID-19 患者住院和死亡的原因。过量的循环促炎细胞因子是严重 COVID-19 的一个特征，现在 Koenis 及其同事表明，在此类患者中某些促消退因子也失衡。虽然来自轻度 COVID-19 患者的血液样本显示专门的促分解脂质介质 (SPM) 有所增加，但来自严重疾病患者的血液样本中这些脂质因子的水平较低。轻症患者吞噬细胞上 SPM 受体的表达也高于重症 COVID-19 患者。并且，与此相符，重症患者活化促炎性吞噬细胞的比例较高。该团队继续表明，接受类固醇地塞米松治疗的患者血液中的 SPM 水平升高。结果表明，在 COVID-19 的严重病例中，SPM 失调，并表明 SPM 调节，无论是通过类固醇给药还是其他药理学手段，都可以促进失控炎症的消退。

几项全基因组关联研究 (GWAS) 已在ADAMTS7基因及其周围的基因间区域作为冠状动脉疾病的风险位点。此外，动物研究表明 ADAMTS7 蛋白既是一种金属蛋白酶又是一种蛋白多糖，具有促动脉粥样硬化的作用。然而，蛋白质的哪个身份负责促进动脉粥样硬化尚不清楚。Mizoguchi 及其同事现在表明 ADAMTS7 的酶促功能是罪魁祸首。该团队用 [a] 催化失活版本的 ADAMTS7 生成小鼠，并将这些动物与完全缺乏 ADAMTS7 或具有完全完整蛋白质（野生型）的动物进行比较。他们发现，在两种不同的动脉粥样硬化模型中，ADAMTS7 蛋白本身或其催化功能的缺失足以减少斑块负担。已知 ADAMTS7 可调节血管平滑肌细胞 (VSMC) 的迁移，研究小组表明，这有助于斑块形成，缺乏全蛋白或仅缺乏催化活性的 VSMC 会损害迁移活性。这些结果共同指出 ADAMTS7 的酶活性是促动脉粥样硬化的，并表明该蛋白质的催化结构域可能是减少动脉粥样硬化的治疗靶点。

发育中的心脏被认为来自两个细胞群——第一个和第二个心脏区域——它们首先在 E7.5 阶段的小鼠胚胎（第 15 天人类胚胎）中被识别出来。控制这些领域发展的基因与先天性心脏缺陷 (CHD) 有关，但有趣的是，由于尚不清楚的原因，CHD 有时也与胎盘异常有关。Zhang 及其同事现在表明，第一个心脏场和胚胎外组织——那些产生卵黄囊和胎盘的组织——有着意想不到的联系。通过谱系追踪实验和单细胞转录组学，该团队发现第一个心脏场由两个中胚层祖细胞来源组成——一个在本质上是胚胎，另一个来自早期原肠胚的胚外和胚胎组织之间的界面。研究小组表明，后一种祖细胞群表达了转录因子 Hand1，除了心场细胞外，还会产生胚外中胚层细胞。这一中胚层祖细胞共享来源的发现不仅模糊了胚胎与其支持组织之间的界限，而且还可以解释胎盘异常与先天性心脏病之间的联系。