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Macrophages are required for adult salamander limb regeneration
Edited* by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 24, 2013 (received for review January 8, 2013)

Abstract
The failure to replace damaged body parts in adult mammals results from a muted growth response and fibrotic scarring. Although infiltrating immune cells play a major role in determining the variable outcome of mammalian wound repair, little is known about the modulation of immune cell signaling in efficiently regenerating species such as the salamander, which can regrow complete body structures as adults. Here we present a comprehensive analysis of immune signaling during limb regeneration in axolotl, an aquatic salamander, and reveal a temporally defined requirement for macrophage infiltration in the regenerative process. Although many features of mammalian cytokine/chemokine signaling are retained in the axolotl, they are more dynamically deployed, with simultaneous induction of inflammatory and anti-inflammatory markers within the first 24 h after limb amputation. Systemic macrophage depletion during this period resulted in wound closure but permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression. Full limb regenerative capacity of failed stumps was restored by reamputation once endogenous macrophage populations had been replenished. Promotion of a regeneration-permissive environment by identification of macrophage-derived therapeutic molecules may therefore aid in the regeneration of damaged body parts in adult mammals.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: james.godwin{at}monash.edu.
Author contributions: J.W.G. designed research; J.W.G. performed research; A.R.P. contributed new reagents/analytic tools; J.W.G. and A.R.P. analyzed data; and J.W.G., A.R.P., and N.A.R. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1300290110/-/DCSupplemental.
Freely available online through the PNAS open access option.