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

Tartrate-resistant acid phosphatase [TRAP, gene acid phosphatase 5 (Acp5; gene name for TRAP)] 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 patients with chronic obstructive pulmonary disease (COPD), 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 wk, higher Acp5 mRNA expression in lung tissue after smoking was mainly driven by transcript Acp5-202, which originates from macrophages. The expression of Acp5-202 correlated with transcription factors previously found to drive proliferation of macrophages. Treating fetal liver progenitor-derived alveolar-like macrophages [Max Planck Institute (MPI; macrophages derived from fetal liver progenitors) macrophages] with cigarette smoke extract resulted in more proliferation compared with 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 Beta-catenin (b-catenin; a signaling protein) compared with nontreated controls. Phosphorylation of b-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 b-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.