Impaired lung NK activity in the lung of Idiopathic Pulmonary Fibrosis patients

Abstract

<b>Rationale:</b> Idiopathic Pulmonary Fibrosis (IPF) is an age-related lung disease. Our group and others had identified the accumulation of senescent fibroblasts and epithelial cells in the lungs of IPF patients. Activated Natural killer lymphocytes (NK) cells have been implicated in the clearance of senescent cells. <b>Methods:</b> The proportion of NK cells and their senescent status was evaluated by flow cytometry. The effect of the lung microenvironment was evaluated using lung fibroblast conditioned media. The NK migration capacity was determine by the expression of chemokine receptors, presence of plasma chemokines and transwell migration assays. A mouse model of NK depletion and bleomycin inducing lung fibrosis was used to asses the relation between the NK cells and the senescent cell clearance. <b>Results:</b> The proportion of NK cells in the IPF lung is reduced and have an impaired gene expression. IPF lung NK cells have increased immunosenescence with IL-6 production. The IPF lung fibroblast conditioned media increases the percent of senescent cells and reduces NK cytotoxic activity. The presence of IL-15 was able to revert the detrimental effect of the IPF CM. Plasma cytokines showed a decreased in NK lung recruitment chemokines and lung NK cells have a reduction in the expression of CCR2. This impaired recruitment may be inducing their accumulation in the blood. In vivo lung fibrosis mouse model with NK depletion showed the importance of NK cells in the resolution of lung fibrosis and clearance of senescent cells. <b>Conclusions:</b> We propose that defects in NK activity could be one of the mechanisms responsible for the perpetration of the accumulation of senescent cells in IPF lungs.