Wound Healing in the PU.1 Null Mouse—Tissue Repair Is Not Dependent on Inflammatory Cells

Abstract

Damage to neonatal and adult tissues always incites an influx of inflammatory neutrophils and macrophages. Besides clearing the wound of invading microbes, these cells are believed to be crucial coordinators of the repair process, acting both as professional phagocytes to clear wound debris and as a major source of wound growth factor signals. Here we report wound healing studies in the PU.1 null mouse, which is genetically incapable of raising the standard inflammatory response because it lacks macrophages and functioning neutrophils. Contrary to dogma, we show that these "macrophageless" mice are able to repair skin wounds with similar time course to wild-type siblings, and that repair appears scar-free as in the embryo, which also heals wounds without raising an inflammatory response. The growth factor and cytokine profile at the wound site is changed, cell death is reduced, and dying cells are instead engulfed by stand-in phagocytic fibroblasts. We also show that hyperinnervation of the wound site, previously believed to be a consequence of inflammation, is present in the PU.1 null wound, too.

Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair

“…26 In wound repair, several lines of reasoning suggest macrophages are the principle effector: (1) responses are seen 3 to 4 days after injury when macrophages are abundant but lymphocytes are rare; (2) Flt1 protein levels were diminished in Wls-deficient macrophages; (3) endogenous immune cells in the ARA are predominantly macrophages 37 ; and (4) similar wound vascular responses are observed in PU.1 2/2 mice that have relatively normal lymphocyte populations. 40 In the wound, it seems counterintuitive that natural mechanisms would exist to suppress angiogenesis and slow repair rates. One hypothesis is that increasing angiogenesis may increase repair rates, although it might also make the wound weaker and more susceptible to a second injury during repair.…”

Differential Roles of Macrophages in Diverse Phases of Skin Repair

“…This dogma has been challenged by recent reports, thereby arguing against an essential role of inflammatory cells in wound repair: early fetal wounds heal with minimal scarring, which is associated with little inflammation (12). Furthermore, wounds in the neonatal PU.1 null mouse, which lacks macrophages and neutrophils (but also B cells, mast cells, eosinophils), heal without scar and, surprisingly, with a similar time course as wild-type siblings (13). However, the need of macrophages for physiological repair in adults is supported in recent wound healing studies in various murine knockout models in which impaired wound healing is associated with an attenuated number of macrophages at the wound site (14)(15)(16)(17)(18).…”

Looking proximally and distally: 100 years of limb regeneration and beyond

“…Antibodies to TGF-b1, 2, or addition of exogenous TGF-b3 administered early in the course of adult mouse skin repair evoke a more regenerative response (Shah et al, 1994(Shah et al, , 1995, while hyaluronidase and PDGF administered to fetal skin shifts the wound response toward scarring (Haynes et al, 1994;Mast et al, 1995). Skin wounds in antibiotic-maintained PU.1 null mice, which lack macrophages and neutrophils, are repaired by regeneration (Martin et al, 2003).…”