Pulmonary fibrosis is a fatal interstitial lung disease marked by irreversible lung structure destruction. Understanding its molecular mechanisms is essential. Cold-inducible RNA-binding protein (CIRBP), a stress-responsive protein, stabilizes mRNA intracellularly and also acts extracellularly. We previously demonstrated that CIRBP is highly expressed in fibrotic lesions of idiopathic pulmonary fibrosis patients, with elevated serum levels correlating with disease progression and poor prognosis. However, its role in fibrosis remains unclear. We investigated CIRBP's function using an in vivo bleomycin (BLM)-induced pulmonary fibrosis mouse model via intratracheal administration and an in vitro model with primary lung fibroblasts. CIRBP expression was markedly upregulated in the fibrotic regions of BLM-treated wild-type (WT) mice. CIRBP-deficient mice showed improved survival, reduced fibrosis, lower hydroxyproline content, and decreased expression of α-SMA and fibronectin. Therapeutic administration of C23, a CIRBP-derived inhibitory peptide, significantly suppressed fibrosis and improved survival in WT mice. In vitro, recombinant CIRBP promoted collagen secretion, fibroblast proliferation, and cell migration, which were inhibited by C23. Mechanistically, CIRBP-induced IL-6 production via TLR2 and TLR4, leading to fibroblast activation through autocrine signaling. These effects were suppressed by C23, TLR2/4 inhibitors, or IL-6 neutralization. Our findings identify CIRBP as a novel profibrotic factor and therapeutic target in pulmonary fibrosis.
Mochizuka et al. (Wed,) studied this question.