An Early Myelosuppression in the Acute Mouse Sepsis Is Partly Outcome-Dependent.

Tomasz Skirecki,Susanne Drechsler,Grażyna Hoser,Mohammad Jafarmadar,Aldona Jeznach,Marcin F Osuchowski,Jerzy Kawiak

doi:10.3389/fimmu.2021.708670

Abstract

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; lineage−ckit+Sca-1+ and short-term HSC suppression was greater in P-DIE versus 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) versus 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.

Highlights

Adult mammals constantly produce mature blood cells from the hematopoietic stem cells in the process of hematopoiesis occurring in the bone marrow (BM) [1]
cecal ligation and puncture (CLP) Outcome Is Associated With Depletion of the Hematopoietic Stem and Progenitor Cells (HSPCs) in the Bone Marrow
In cells from P-DIE mice, IL-6 transcripts were upregulated by three-fold in comparison with P-SUR, whereas no differences were present for IL-1b and TNF expression (Figure 6). These results indicate that the BM cytokine milieu is selectively altered in dying septic mice and hematopoietic stem and progenitor cells (HSPCs) contribute to this differential localized cytokine production. This mouse study addressed a gap in human sepsis by investigating whether the HSPCs in their bone marrow niche are differentially affected with regard to outcome

Summary

Introduction

Adult mammals constantly produce mature blood cells from the hematopoietic stem cells in the process of hematopoiesis occurring in the bone marrow (BM) [1]. The majority of hematopoietic stem and progenitor cells (HSPCs) are located in specialized niches in the BM, which protect them from oxidative injury and tightly control the hematopoiesis via multiple molecular. It has been shown that through an expression of the toll-like receptors (TLRs), HSCs can sense microbial infections and locally differentiate to myeloid cells contributing to a local immune response [3, 4]. Microbial compounds are sensed by TLRs and nucleotide-binding oligomerization domain containing (NOD)-like receptors located on the endothelial cells of the BM niche, which in turn produce the granulocyte-colony stimulating factor (G-CSF) inducing proliferation and differentiation of HSPCs [6]. G-CSF has been shown to drive mobilization of HSPCs from the BM niche to the blood and subsequently the spleen [7]

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Conclusion