IL-6-elafin genetically modified macrophages as a lung immunotherapeutic strategy against Pseudomonas aeruginosa infections.

Abstract

Pseudomonas aeruginosa (P.a) infections are a major public health issue in ventilator-associated pneumoniae, cystic fibrosis and chronic obstructive pulmonary disease exacerbations. P.a is multidrug resistant and there is an urgent need to develop new therapeutic approaches. Here, we evaluated the effect of direct pulmonary transplantation of gene-modified (elafin and IL-6) syngeneic macrophages in a mouse model of acute of P.a infection. Wild type (WT) or Elafin-transgenic (eTg) alveolar macrophages (AMs) or bone marrow derived macrophages (BMDMs) were recovered from broncho-alveolar lavage or generated from WT or eTg mice bone marrow. Cells were modified with adenovirus IL-6 (Ad-IL6), characterized in vitro and transferred by oropharyngeal instillation in the lungs of naïve mice. The protective effect was assessed during P.a acute infection (survival studies, mechanistic studies of the inflammatory response). We show that a single bolus of syngeneic AMs or BMDMs genetically modified provided protection in our pneumonia P.a-induced model. Mechanistically, Elafin-modified AMs had an IL-6-IL-10-IL-4R-IL-22-antimicrobial molecular signature which, in synergy with IL-6, enhanced epithelial cell proliferation and tissue repair in the alveolar unit. We believe that this innovative cell therapy strategy could be of value in acute bacterial infections in the lung.