IGF-1 Receptor Signaling Regulates Type II Pneumocyte Senescence and Resulting Macrophage Polarization in Lung Fibrosis

Abstract

Purpose: Type II pneumocyte (alveolar epithelial cells type II [AECII]) senescence has been implicated in the progression of lung fibrosis. The capacity of senescent cells to modulate pulmonary macrophages to drive fibrosis is unexplored. Insulin-like growth factor-1 receptor (IGF-1R) signaling has been implicated as a regulator of senescence and aging.

Methods and Materials: Mice with an AECII-specific deletion of IGF-1R received thoracic irradiation (n >= 5 per condition), and the effect of IGF-1R deficiency on radiation-induced AECII senescence and macrophage polarization to an alternatively activated phenotype (M2) was investigated. IGF-1R signaling, macrophage polarization, and senescence were evaluated in surgically resected human lung (n = 63).

Results: IGF-1R deficient mice demonstrated reduced AECII senescence (senescent AECII/field; intact: 7.25% +/- 3.5% [ mean +/- SD], deficient: 2.75% +/- 2.8%, P = .0001), reduced accumulation of M2 macrophages (intact: 24.7 +/- 2.2 cells/field, deficient: 15.5 +/- 1.2 cells/field, P = .0086), and fibrosis (hydroxyproline content; intact: 71.9 +/- 21.7 mu g/lung, deficient: 31.7 +/- 7.9, P = .0485) after irradiation. Senescent AECII enhanced M2 polarization in a paracrine fashion (relative Arg1 mRNA, 0 Gy: 1.0 +/- 0.4, 17.5 Gy: 7.34 +/- 0.5, P < .0001). Evaluation of surgical samples from patients treated with chemoradiation demonstrated increased expression of IGF-1 (unirradiated: 10.2% +/- 4.9% area, irradiated: 15.1% +/- 11.5%, P +/- .0377), p21 (unirradiated: 0.013 +/- 0.02 histoscore, irradiated: 0.084 +/- 0.09 histoscore, P +/- .0002), IL-13 (unirradiated: 13.7% +/- 2.8% area, irradiated: 21.7% +/- 3.8%, P < .0001), and M2 macrophages in fibrotic regions relative to nonfibrotic regions (unirradiated: 11.4 +/- 12.2 CD163 thorn cells/core, irradiated: 43.1 +/- 40.9 cells/core, P = .0011), consistent with findings from animal models of lung fibrosis.

Conclusions: This study demonstrates that senescent AECII are necessary for the progression of pulmonary fibrosis and serve as a targetable, chronic stimuli for macrophage activation in fibrotic lung. Published by Elsevier Inc.