Abstract
The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice pretreated with tamoxifen at 80 mg/kg/d for three days and infected with Acinetobacter baumannii, Pseudomonas aeruginosa, or Escherichia coli in peritoneal sepsis models showed reduced release of the monocyte chemotactic protein-1 (MCP-1) and its signaling pathway interleukin-18 (IL-18), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from the bone marrow to the blood. Indeed, pretreatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood, and increased mice survival from 0% to 60–100%. Together, these data show that tamoxifen presents therapeutic efficacy against MDR A. baumannii, P. aeruginosa, and E. coli in experimental models of infection and may be a new candidate to be repurposed as a treatment for GNB infections.
Highlights
To determine whether bacterial infection influences circulating immune cells from the bone marrow in response to monocyte chemotactic protein-1 (MCP-1) and IL-18, a MCP-1 controller [16], we intraperitoneally administered A. baumannii, P. aeruginosa, and E. coli to mice and measured the proportions of myeloid cells CD11b+, inflammatory monocytes CD11b+Ly6Chi, and neutrophils
The percentages of these immune cells, from a total of 1.6 × 106 cells/mL, were decreased less after infection with A. baumannii, P. aeruginosa, and E. coli for 24 h (Table S1); indicating that the increase of circulating monocytes and neutrophils did not proceed from the splenic reservoir [22,23]
We suggest that the reduction of IL-18 secretion by tamoxifen may drive the reduction of MCP-1 release through a reduction of ERK phosphorylation, which would contribute to efficient reduction of the migration of inflammatory monocytes and neutrophils from the bone marrow to the blood
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Infections caused by Gram-negative bacilli (GNB) such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli represent an increasing worldwide problem. Sepsis is a major cause of mortality in acute infections, characterized by a systemic inflammatory response syndrome caused by them [1,2]. In the United States the incidence of sepsis was increased from 50–95 to 535 cases per 100,000 inhabitants between 2003 and
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