Skirecki Tomasz, Drechsler Susanne, Jeznach Aldona, Hoser Grażyna, Jafarmadar Mohammad, Kawiak Jerzy, Osuchowski Marcin F
Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education, Warsaw, Poland.
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the Allgemeine Unfallversicherungsanstalt (AUVA) Research Center, Vienna, Austria.
Front Immunol. 2021 Jul 22;12:708670. doi: 10.3389/fimmu.2021.708670. eCollection 2021.
Adult hematopoietic stem and progenitor cells (HSPCs) respond to bacterial infections by expansion to myeloid cells. Sepsis impairs this process by suppressing differentiation of stem cells subsequently contributing to an ineffective immune response. Whether the magnitude of HSPCs impairment in sepsis is severity-dependent remains unknown. This study investigated dynamics of the HSPC immune-inflammatory response in the bone marrow, splenic, and blood compartments in moribund and surviving septic mice. The 12-week-old outbred CD-1 female mice (n=65) were subjected to a cecal ligation and puncture (CLP) sepsis, treated with antibiotics and fluid resuscitation, and stratified into predicted-to-die (P-DIE) and predicted-to-survive (P-SUR) cohorts for analysis. CLP strongly reduced the common myeloid and multipotent progenitors, short- and long-term hematopoietic stem cell (HSC) counts in the bone marrow; lineageckitSca-1 and short-term HSC suppression was greater in P-DIE P-SUR mice. A profound depletion of the common myeloid progenitors occurred in the blood (by 75%) and spleen (by 77%) of P-DIE. In P-SUR, most common circulating HSPCs subpopulations recovered to baseline by 72 h post-CLP. Analysis of activated caspase-1/-3/-7 revealed an increased apoptotic (by 30%) but not pyroptotic signaling in the bone marrow HSCs of P-DIE mice. The bone marrow from P-DIE mice revealed spikes of IL-6 (by 5-fold), CXCL1/KC (15-fold), CCL3/MIP-1α (1.7-fold), and CCL2/MCP-1 (2.8-fold) P-SUR and control (TNF, IFN-γ, IL-1β, -5, -10 remained unaltered). Summarizing, our findings demonstrate that an early sepsis-induced impairment of myelopoiesis is strongly outcome-dependent but varies among compartments. It is suggestive that the HSCPC loss is at least partly due to an increased apoptosis but not pyroptosis.
成年造血干细胞和祖细胞（HSPCs）通过向髓系细胞扩增来应对细菌感染。脓毒症通过抑制干细胞分化损害这一过程，进而导致免疫反应无效。脓毒症中HSPCs损害的程度是否依赖于严重程度尚不清楚。本研究调查了濒死和存活的脓毒症小鼠骨髓、脾脏和血液中HSPC免疫炎症反应的动态变化。将12周龄的远交系CD-1雌性小鼠（n = 65）进行盲肠结扎穿刺（CLP）诱导脓毒症，给予抗生素治疗和液体复苏，并分为预测死亡（P-DIE）和预测存活（P-SUR）队列进行分析。CLP显著降低了骨髓中常见髓系祖细胞和多能祖细胞、短期和长期造血干细胞（HSC）的数量；P-DIE小鼠中谱系⁻ckit⁺Sca-1⁺和短期HSC的抑制作用比P-SUR小鼠更大。P-DIE小鼠的血液（减少75%）和脾脏（减少77%）中常见髓系祖细胞出现显著耗竭。在P-SUR小鼠中，大多数常见的循环HSPC亚群在CLP后72小时恢复到基线水平。对活化的半胱天冬酶-1/-3/-7的分析显示，P-DIE小鼠骨髓HSCs中凋亡信号增加（30%），但无细胞焦亡信号。P-DIE小鼠的骨髓中IL-6（增加5倍）、CXCL1/KC（15倍）、CCL3/MIP-1α（1.7倍）和CCL2/MCP-1（2.8倍）出现峰值，而P-SUR和对照组（TNF、IFN-γ、IL-1β、-5、-10）保持不变。总之，我们的研究结果表明，早期脓毒症诱导的骨髓生成损害强烈依赖于结局，但在不同部位有所不同。提示HSCPC的损失至少部分是由于凋亡增加而非细胞焦亡。
