细菌感染可以激活和动员造血干细胞和祖细胞(HSPCs)从骨髓(BM)到脾脏,称为髓外造血(EMH)的过程。最近的研究表明,共生细菌不仅调节宿主免疫系统,而且调节造血稳态。然而,肠道微生物对造血病理的影响尚不清楚.这里,我们发现全身单次注射Akkermansia黏蛋白(A.Mi.),一种粘蛋白降解细菌,快速激活BM骨髓生成和缓慢但持久的肝脾肿大,以功能性HSPCs的扩增和分化为特征,我们称之为延迟EMH。机械上,由A.m.触发的延迟EMH完全由MYD88/TRIF先天免疫信号通路介导,持续刺激脾骨髓细胞分泌白细胞介素(IL)-1α,反过来,激活表达IL-1受体(IL-1R)的脾HSPC。Toll样受体-2和-4(TLR2/4)或IL-1α的遗传缺失部分地减少A.m.-诱导延迟EMH,而两条途径的抑制可减轻脾肿大和EMH。我们的结果表明,协同IL-1R和TLR介导的信号调节共生细菌驱动的EMH,这可能与某些自身免疫性疾病有关。
Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to the spleen, a process termed extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria regulate not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbes on hematopoietic pathology remains unclear. Here, we find that systemic single injections of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium, rapidly activate BM myelopoiesis and slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we term delayed EMH. Mechanistically, delayed EMH triggered by A. m. is mediated entirely by the MYD88/TRIF innate immune signaling pathway, which persistently stimulates splenic myeloid cells to secrete interleukin (IL)-1α, and in turn, activates IL-1 receptor (IL-1R)-expressing splenic HSPCs. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) or IL-1α partially diminishes A. m.-induced delayed EMH, while inhibition of both pathways alleviates splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders.