TRAPping the effects of tobacco smoking: the regulation and function of Acp5 expression in lung macrophages.

Abstract

Tartrate-resistant acid phosphatase (TRAP, gene Acp5) is highly expressed in alveolar macrophages with proposed roles in lung inflammation and lung fibrosis development. We previously showed that its expression and activity are higher in lung macrophages of smokers and COPD patients, suggesting involvement in smoke-induced lung damage. In this study we explored the function of TRAP and regulation of its different mRNA transcripts (Acp5 201-206) in lung tissue exposed to cigarette smoke to elucidate its function in alveolar macrophages. In mice exposed to cigarette smoke or air for 4-6 weeks, higher Acp5 mRNA expression in lung tissue after smoking was mainly driven by transcript Acp5-202, which originates from macrophages. Expression of Acp5-202 correlated with transcription factors previously found to drive proliferation of macrophages. Treating fetal liver progenitors-derived alveolar-like macrophages (MPI macrophages) with cigarette smoke extract resulted in more proliferation compared to nontreated cells. In contrast, Acp5-deficient MPI macrophages and MPI macrophages treated with a TRAP inhibitor proliferated significantly less than control macrophages. Mechanistically this lack of proliferation after TRAP inhibition was associated with higher presence of phosphorylated β-catenin compared to nontreated controls. Phosphorylation of β-catenin is known to mark it for ubiquitination and degradation by the proteasome, preventing its activity in promoting cell proliferation. In conclusion, our findings provide strong evidence for TRAP stimulating alveolar macrophage proliferation by dephosphorylating β-catenin. By driving proliferation, TRAP likely helps sustain alveolar macrophage populations during smoke exposure, either compensating for their loss due to smoking or increasing their numbers to better manage smoke-induced damage.