Alcohol Impairs the Myeloid Proliferative Response to Bacteremia in Mice by Inhibiting the Stem Cell Antigen-1/ERK Pathway

Abstract

Enhancement of stem cell antigen-1 (Sca-1) expression by myeloid precursors promotes the granulopoietic response to bacterial infection. However, the underlying mechanisms remain unclear. Extracellular-regulated kinase (ERK) pathway activation strongly enhances proliferation of hematopoietic progenitor cells. Here, we investigated the role of Sca-1 in promoting ERK-dependent myeloid lineage proliferation and the effects of alcohol on this process. Thirty minutes after intraperitoneal injection of alcohol, mice received intravenous challenge with 5 × 107 E.coli for 8 or 24 h. A subset of mice received intravenous BrdU injection 20 h post challenge. Bacteremia increased Sca-1 expression, ERK activation, and proliferation of myeloid and granulopoietic precursors. Alcohol administration suppressed this response and impaired granulocyte production. Sca-1 expression positively correlated with ERK activation and cell cycling, but negatively correlated with myeloperoxidase content in granulopoietic precursors. Alcohol intoxication suppressed ERK activation in granulopoietic precursors and proliferation of these cells during bacteremia. Granulopoietic precursors in Sca-1−/− mice failed to activate ERK signaling and could not increase CFU-GM activity following bacteremia. These data indicate that Sca-1 expression promotes ERK-dependent myeloid cell proliferation during bacteremia. Suppression of this response could represent an underlying mechanism for developing myelosuppression in alcohol abusing hosts with severe bacterial infection.

Stem Cell Antigen 1 Protects Against Cardiac Hypertrophy and Fibrosis After Pressure Overload

“…34 In granulopoietic precursors, Sca-1 expression positively correlated with ERK activation, and a lack of Sca-1 led to ERK inactivation. 35 However, here we showed that Sca-1 negatively regulated ERK activation in a hypertrophic heart, which seems to be inconsistent with previous data. A potential reason for the discrepancy is that the effect of Sca-1 on the ERK pathway depends on the cell, tissue, and disease background.…”

Toll-Like Receptor 4/Stem Cell Antigen 1 Signaling Promotes Hematopoietic Precursor Cell Commitment to Granulocyte Development during the Granulopoietic Response to Escherichia coli Bacteremia

“…TLR4 deletion abolished these increases. Previously, we have reported that the Sca-1 response penetrates into the committed granulopoietic progenitor compartment in the bone marrow during bacteremia (12,13). Our current results showed that LPS also increased BrdU incorporation into the Sca-1 ϩ Gr1 ϩ cell subpopulation and total Gr1 ϩ cells in the culture system.…”

“…Previous studies have shown that HSCs from Sca-1 null mice exhibit reduced potential for myeloid lineage development (40). Furthermore, the activation of cell proliferation and granulocyte development in myeloid and granulopoietic progenitors in response to bacteremia is attenuated with Sca-1 ablation (12,13). In this study, the number of granulopoietic progenitors expressing a low level of surface Gr1 tended to decrease in the bone marrow of Sca-1 null mice following bacteremia, which was accompanied by a severe reduction of the marrow granulocyte pool following bacteremia.…”

“…This upregulation of Sca-1 expression correlates with expansion of the marrow primitive hematopoietic precursor cell pool and enhancement of granulocyte lineage development. Disruption of Sca-1 upregulation impairs the granulopoietic response to severe bacterial infection (11)(12)(13). At this time, however, the cell signaling mechanisms underlying the programming of primitive hematopoietic precursor cells for their enhancement of granulocyte lineage commitment during the process of host defense against bacterial infection remain unclear.…”

Production and Differentiation of Myeloid Cells Driven by Proinflammatory Cytokines in Response to Acute Pneumovirus Infection in Mice

“…However, previous studies have demonstrated that inflammatory cytokines (including both TNFα and IFNγ) increase Sca-I expression on multiple hematopoietic cells [49], making conclusions based on phenotypic analysis alone problematic. Furthermore, recent evidence suggests that Sca-I induction on myeloid precursors plays an important functional role in driving the granulopoietic response to bacterial infection [50,51]. Increased Sca-I expression results in an apparent increase in phenotypic HSCs (if HSCs are defined based on LSK surface staining alone), emphasizing the importance of performing functional assays to quantify HSCs.…”