Abstract
In response to various environmental signals, macrophages (MΦ) acquire distinct functional phenotypes that have been classified as classical MΦ and alternatively activated MΦ (AAM). AAM cells sustain tissue repair, whereas their depletion contributes to aberrant wound healing.
The current study was aimed at determining whether AAM polarization participated in epithelium repair and in lung fibrosis regulation. To this aim, we used the in vivo model of lung epithelium injury induced by the intra-peritoneal injection of naphthalene in mice.
Epithelium repair phase was accompanied by an increased expression in bronchoalveolar lavage (BAL) cells, of mRNAs encoding the AAM markers (CD206, FIZZ-1 and YM1), and the AAM-derived mediators, MMP-12, CCL2 and elastin. FACS analysis on BAL cells demonstrated a significant increase in the number of monocytes and AAM cells, during the phase that proceeded complete epithelium repair (days 6 to 15).
To define the role of AAM in epithelium repair, we depleted MΦ by administering intra-nasally liposome clodronate to naphthalene-injected mice on days 2, 5 and 8. MΦ-depleted mice displayed impaired epithelium repair, excessive production of fibrogenic mediators (IL-6 and CCL2) and lower levels of TIMP-1 in the lung, and enhanced collagen deposition at days 21 and 35, as compared to control mice. Intra-tracheal adoptive transfer of purified AAM to MΦ-depleted mice on day11 after naphthalene administration restored epithelium repair and suppressed lung fibrosis.
We conclude that lung epithelium repair is accompanied by MΦ polarization towards an AAM phenotype, essential for driving epithelium repair and for preventing tissue fibrosis.
- © 2014 ERS