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

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.

Establishment and Effectiveness Evaluation of a Scoring System-RAAS (RDW, AGE, APACHE II, SOFA) for Sepsis by a Retrospective Analysis

“…Sepsis is a serious, life-threatening syndrome that is one of the leading causes of death in hospitals. 1 , 2 Sepsis was also among the leading causes of the death associated with COVID-19. 3 Despite significant advances in critical care, sepsis still has a relatively high short-term mortality rate due to organ failure due to a dysregulated response to infection.…”

The European Shock Society Meets the Immunosep Consortium for Personalized Sepsis Treatment

“…Experimental models of sepsis in wild-type and humanized mice were used to investigate changes in the hematopoietic compartment (3,4). These studies have identified that increased Notch-1 and IL-6 signaling in the bone marrow contributes to impaired hematopoiesis (5). Interestingly, the IL-6 level in the bone marrow milieu was increased only in mice with the most severe sepsis.…”

Survivors of polymicrobial sepsis are refractory to G-CSF-induced emergency myelopoiesis and hematopoietic stem and progenitor cell mobilization

“…In models of sepsis, including cecal ligation and puncture (CLP), fecal slurry models, or endotoxemia, rapid production of myeloid cells and selective expansion of myeloid-biased progenitors have been observed ( Scumpia et al., 2010 ) and are associated with survival ( Cuenca et al., 2015 ). Phenotypic HSPCs are reduced in the bone marrow (BM) during acute disease ( Darden et al., 2021 ; Morales-Mantilla et al., 2022 ; Skirecki et al., 2015 ; 2021 ), in part due to their mobilization and/or rapid differentiation, highlighting the profound requirement and consumption of innate immune cells during sepsis. However, even months after surviving acute sepsis, mice contain an expanded pool of granulocyte-monocyte progenitor cells (MPP GM s), suggesting sustained myelopoiesis post-sepsis ( Bomans et al., 2018 ).…”