Idiopathic pulmonary fibrosis (IPF) is a progressive and highly lethal inflammatory
interstitial lung disease characterized by aberrant extracellular matrix deposition. Macrophage activation by
cytokines released from repetitively injured alveolar epithelial cells regulates the inflammatory response, tissue remodeling, and
fibrosis throughout various phases of IPF. Our previous studies demonstrate that
nuclear factor of activated T cells cytoplasmic member 3 (
NFATc3) regulates a wide array of macrophage genes during
acute lung injury pathogenesis. However, the role of
NFATc3 in IPF pathophysiology has not been previously reported. In the current study, we demonstrate that expression of
NFATc3 is elevated in lung tissues and pulmonary macrophages in mice subjected to
bleomycin (BLM)-induced
pulmonary fibrosis and IPF patients. Remarkably,
NFATc3 deficiency (
NFATc3+/-) was protective
in bleomycin (BLM)-induced
lung injury and
fibrosis. Adoptive transfer of
NFATc3+/+ macrophages to
NFATc3+/- mice restored susceptibility to BLM-induced
pulmonary fibrosis. Furthermore, in vitro treatment with
IL-33 or
conditioned medium from BLM-treated epithelial cells increased production of CCL2 and CXCL2 in macrophages from
NFATc3+/+ but not
NFATc3+/- mice. CXCL2 promoter-pGL3
Luciferase reporter vector showed accentuated reporter activity when co-transfected with the
NFATc3 expression vector. More importantly, exogenous administration of recombinant CXCL2 into
NFATc3+/- mice increased fibrotic markers and exacerbated IPF phenotype in BLM treated mice. Collectively, our data demonstrate, for the first time, that
NFATc3 regulates
pulmonary fibrosis by regulating CCL2 and CXCL2 gene expression in macrophages.