Neutrophils are described as the first class of infiltrating immune cells at the site of injury, helping to control infection and remove debris. Despite this necessary function, excessive release of enzymes by neutrophils, such as elastase, can be damaging to surrounding tissue, delaying rates of healing and increasing the risk of scar formation [16
]. For these reasons, the need for neutrophil infiltration following injury is heavily debated. Supporting an inhibitory effect of neutrophils on wound repair, in vivo
neutrophil depletion in mice with rabbit anti-mouse sera prior to injury accelerated re-epithelialization through day 3 post injury [18
]. These results by Dovi et al.
are supported by earlier findings that conclude that neutrophils are either dispensable in cutaneous repair [20
] or that their excessive presence is detrimental to the healing process [21
]. In the later study, impaired healing in a murine model of diabetes was associated with enhanced macrophage inflammatory protein-2 production and a concomitant protracted infiltration of neutrophils at the site of injury [21
]. Together, these data suggest that neutrophils may be deleterious by delaying the resolution of the proinflammatory phase and preventing progression into the proliferative phase of wound repair.
Extending the argument for a destructive role of neutrophil recruitment to sites of aseptic injury are fetal wound-healing models. Fetal wound healing is characterized by a markedly reduced inflammatory response, including limited neutrophil recruitment at injury sites, swifter rates of wound closure and minimal, if any, scarring [4
]. It is often suggested that attempting to mimic these early fetal conditions might enhance wound closure. However, one must consider how the aseptic intrauterine environment differs drastically from wound healing in a clinical setting, where commensal dermatopathogens have direct access to sites of cutaneous injury. Thus, the early infiltration of neutrophils is critical to aid in eradication of the bacteria and debridement of the wound site. While this may delay repair and promote fibrosis, it is undeniable that these antimicrobial functions are crucial to control infection, and thus careful consideration should be taken with regards to the modulation of neutrophils.
Contrary to the work above, several other studies have demonstrated a need for neutrophil recruitment to the site of injury. In support of neutrophil-dependent wound healing, mice lacking the CXCR2 receptor responsible for neutrophil chemotaxis have an expected impairment in neutrophil recruitment to the site of injury [22
]. Interestingly, this was accompanied by decreased re-epithelialization and angiogenesis [22
]. These effects may be a direct reflection of the loss of CXCR2 on keratinocytes and fibroblasts, as this receptor is also important in their migration, in addition to neutrophil chemotaxis. It would be of interest to examine a conditional, tissue-specific knockout to further elucidate the respective contributions of CXCR2-mediated neutrophil recruitment and the migration of cells critical to re-epithelialization.
Aging studies have demonstrated delayed wound closure with increasing age, and also support the necessity for neutrophil infiltration for efficient wound closure as neutrophil depletion further delays wound closure in older mice [23
]. In addition, topical application of isolated peritoneal neutrophils following injury or intravenous injection of granulocyte-colony stimulating factor (G-CSF) prior to wounding enhanced wound closure in aged mice to a comparable time frame seen in young mice [23
]. These data provide an interesting point of contention in the argument regarding neutrophil necessity. The differential neutrophil requirement observed in fetal, young and aged mice may highlight an aging difference reflective of the immunosenescent phenotype of the elderly or the enhanced proliferative capacity in utero
. Thus, in neutropenic or immunocompromised individuals incapable of recruiting adequate numbers of neutrophils to sites of injury, topical or systemic G-CSF may mitigate infectious complications. On the other hand, in young, healthy individuals, decreasing the neutrophil flux at sites of injury by increasing macrophage infiltration and efferocytosis with use of mesenchymal stem cells [24
] may improve rates of wound closure. While the absolute necessity of neutrophils in cutaneous injury remains in question, taken together, these data suggest that a delicate balance of neutrophil infiltration is required for efficient wound closure.