Contribution of Progranulin to Protective Lung Immunity During Bacterial Pneumonia.

ABSTRACT

Background: Progranulin (PGRN) is an important immunomodulatory factor in a variety of inflammatory diseases. However, its role in pulmonary immunity against bacterial infection remains unknown. Methods: Pneumonia was induced in PGRN-deficient and normal wild-type mice using Pseudomonas aeruginosa or Staphylococcus aureus, and we assessed the effects of PGRN on survival, bacterial burden, cytokine and chemokine production, and pulmonary leukocyte recruitment after bacterial pneumonia. Results: Patients with community-acquired pneumonia displayed elevated PGRN levels. Likewise, mice with Gram-negative and Gram-positive pneumonia had increased PGRN production in the lung and circulation. Progranulin deficiency led to increased bacterial growth and dissemination accompanied by enhanced lung injury and mortality in bacterial pneumonia, which was associated with impaired recruitment of macrophages and neutrophils in the lung. The reduced number of pulmonary macrophages and neutrophils observed in PGRN-deficient mice was related to a reduction of CCL2 and CXCL1 in the lungs after bacterial pneumonia. Importantly, therapeutic administration of PGRN improved mortality in severe bacterial pneumonia. Conclusions: This study supports a novel role for PGRN in pulmonary immunity and suggests that treatment with PGRN may be a viable therapy for bacterial pneumonia.