Androstenetriol enhances lung macrophage host defense against bacterial pneumonia in mice

Abstract

The active metabolite of dihydroepiandrosterone, 17beta‐androstenetriol (AET), has potent immunomodulatory effects but its potential to improve host defense against the common problem of bacterial pneumonia has not been studied. Mice (C57BL/6, male) were pre‐treated with AET (0.5 mg, s.c.) or vehicle before infection with Strep. pneumoniae (serotype 3, 100K CFU, i.n.). Evaluation showed 8‐fold improved bacterial clearance at 24 h (p <.001, n>20/group) accompanied by decreased inflammation (5‐fold fewer neutrophils in lung lavage samples at 24 h, p < .001). Secondary bacterial pneumonia after influenza remains a major clinical problem. AET treatment of mice on day 7 after non‐lethal influenza infection produced resulted in 15‐fold improved bacterial clearance (p <.001, n >5/group). Survival analysis showed 37% survival in AET‐treated vs. 0% survival in vehicle‐treated mice in this model of secondary pneumococcal pneumonia. In vitro, AET improved macrophage killing of bacteria in vitro (e.g. % bacteria alive after ingestion, vehicle vs AET‐treated: 54 ± 8 vs. 36 ± 7, n>5). To explore mechanisms, we analyzed the role of MARCO, a macrophage scavenger receptor with important functions in host defense against bacteria. Western blot analysis showed that in vitro AET increased MARCO expression in both murine and human macrophages. Comparison of bacterial clearance after vehicle or AET pre‐treatment showed marked improvement in wild‐type mice, but no benefit in MARCO −/− mice. We conclude that AET enhances innate resistance to primary and secondary pneumococcal pneumonia, in part through increased expression of the scavenger receptor MARCO, and is a potential immunomodulator for improving lung host defense against bacterial pneumonia.Support or Funding InformationNIH ES00002 ES11008