Erythropoietin Promotes Infection Resolution and Lowers Antibiotic Requirements in E. coli- and S. aureus-Initiated Infections

Abstract

Endogenous mechanisms underlying bacterial infection resolution are essential for the development of novel therapies for the treatment of inflammation caused by infection without unwanted side effects. Herein, we found that erythropoietin (EPO) promoted the resolution and enhanced antibiotic actions in Escherichia coli (E. coli)- and Staphylococcus aureus (S. aureus)-initiated infections. Levels of peritoneal EPO and macrophage erythropoietin receptor (EPOR) were elevated in self-limited E. coli-initiated peritonitis. Myeloid-specific EPOR-deficient mice exhibited an impaired inflammatory resolution and exogenous EPO enhanced this resolution in self-limited infections. Mechanistically, EPO increased macrophage clearance of bacteria via peroxisome proliferator-activated receptor γ (PPARγ)-induced CD36. Moreover, EPO ameliorated inflammation and increased the actions of ciprofloxacin and vancomycin in resolution-delayed E. coli- and S. aureus-initiated infections. Collectively, macrophage EPO signaling is temporally induced during infections. EPO is anti-phlogistic, increases engulfment, promotes infection resolution, and lowers antibiotic requirements.

Extracellular CIRP-Impaired Rab26 Restrains EPOR-Mediated Macrophage Polarization in Acute Lung Injury

“…While the anti-inflammatory cytokine IL-10 was also induced, it gradually decreased and remained high at day 5. In this model, BALF neutrophils increased rapidly, peaked at day 2, followed by a gradual decrease to background levels at around day 5, with a resolution interval (Ri, T 50 –T max ) ( 19 ), which is the time when 50% of neutrophils are lost from BALF, of approximately 52.7 h ( Figure 1F ).…”

“…Thus, neutrophil (Ly6G + F4/80 - ) numbers in BALF could be figured out during the course of ALI/ARDS, and resolution indices were calculated. The resolution of acute inflammation was defined by the following resolution indices: ψ max , the maximal neutrophil numbers in BALF; T max , the time point of maximal neutrophil numbers in BALF; R 50 , 50% of maximal neutrophil numbers; T 50 , the time point when BALF neutrophil numbers reduced to 50% of the maximum; Ri (resolution interval, T 50 –T max ), the time period when 50% neutrophils are lost from BALF ( 19 ).…”

“…Further study displayed that EPOR is also located at the cell surface of macrophages (14,15). EPO could promote the expression of EPOR in macrophages and then suppress inflammatory gene expression (15)(16)(17)(18)(19) and promote apoptotic cell clearance (15). Yang et al (20) revealed that activation of EPOR/ Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling by EPO suppressed the M1 phenotype and shifted macrophage polarization toward the M2 phenotype in the presence of IL-4.…”

“…Further study displayed that EPOR is also located at the cell surface of macrophages ( 14 , 15 ). EPO could promote the expression of EPOR in macrophages and then suppress inflammatory gene expression ( 15 – 19 ) and promote apoptotic cell clearance ( 15 ). Yang et al.…”

Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance

“…The kidney was scored by measuring glomeruli size in 5 fields per sample and then averaging groups. Skin and lung injury scores were quantified as previously described ( 19 , 20 ). For immunofluorescent staining, paraffin-embedded tissue blocks were cut into 4-μm sections.…”