Table 1.
Summary of Immune Cell Roles in Tissue Healing and Clinical Outcomes
| Role in healing (preclinical) | Clinical relevance | |
|---|---|---|
| Neutrophils | Neutrophil depletion delays/impairs healing2 Neutrophils enhanced angiogenesis in early wounds3 |
Dominance of neutrophil-derived proteases in recalcitrant venous ulcers, high levels in wound exudate associated with poor wound healing4 |
| Innate lymphoid cells (ILCs) | Barrier functions in tissue-dependent contexts dictate the roles of ILCs5,6 ILC1: proinflammatory through the secretion of IFNγ ILC2: innate immune response to intestinal parasitic worm clearance and ties to pathogenesis of asthma and allergy7 ILC3: intestinal barrier maintenance, promotion of fibrosis with synthetic biomaterials, or inflammation resolution in the lung8 |
Group 2 ILCs are enriched in atopic dermatitis (AD) skin lesions ILC2s in AD wounds may be a distinct population or in a different state of activation compared with ILC2s present in healthy skin9 RORγ+-CD127+CD3− ILC infiltration in human skin following wounding with punch biopsy enhances healing10 |
| NK cells | Defense against viral infection CD56dim and CD56bright NK cell classifications; CD56dim are cytotoxic, while CD56bright cells secrete mediating cytokines11 Clearance of senescent cells12 |
In patients undergoing endovascular aneurysm repair (EVAR), lower NK cell numbers correlated with negative long-term outcomes from EVAR (increased mortality)13 Sleep deprivation reduces NK cell number and NK cell activity14 |
| Eosinophils | Produce IL-4 and IL-13 direct stem cell fate in muscle regeneration15 Secrete IL-4 in liver injury to promote regeneration16 |
In burn wounds, high eosinophil infiltration is linked with increased wound healing. The absence of eosinophil infiltration leads to a poor prognosis and death in patients who did achieve a certain amount of eosinophils within 1 week following the burn17 However, aged patients with burn wounds present with increased eosinophil infiltration during early stages of healing, resulting in increased healing time compared with younger patients18 |
| Monocytes | CCR2hiCX3CR1low monocytes transition to CCR2lowCX3CR1hi to enter the injury site19 | CD33+CD14+CD11b+HLA-DRlow monocyte populations increased following hip surgery and an upregulation of STAT3 signaling correlated with surgical recovery20 |
| Macrophages | Required for salamander limb regeneration21; M2/alternatively activated macrophage phenotypes M1/proinflammatory macrophage phenotypes22,23 |
M1 macrophages, in chronic venous leg ulcers (CVUs), inhibited tissue repair24 M2 macrophages are also associated with accelerating bone healing in patients with traumatic brain injury25 |
| γδ T cells | Regulate macrophage homing Can induce IL-4 to regulate the macrophage phenotype (specific subsets of γδ T cells within injury)26,27 Modulate repair mechanisms in the wound environment through expression of IL-17 and IL-22 in CCl4, which induced liver fibrosis26,28 |
Psoriasis: γδ T cell frequency is increased compared with healthy controls, Psoriasis-associated γδs secrete higher levels of IL-17 than healthy control γδ− T cells29 |
| Immunologically activated fibroblasts | Secrete cytokines,30 orchestrate monocyte differentiation into macrophages31 Proangiogenic capabilities32 |
IFNγ, MCP-1, GM-CSF, and bFGF were overexpressed by wound fibroblasts in patients with chronic wounds compared with patients with well-healing wounds33 |
| CD8+ T cells | Depletion of CD8+ T cells results in wounds with increased mechanical toughness, linked to regulation fibroblasts and macrophages during wound healing34 | Elevated CD8+ T cells in the patient's blood and at the fracture site were associated with impaired bone repair35,36 |
| Tregs | Control effector T cell and neutrophil activity Regulate macrophage and monocyte phenotypes to anti-inflammatory states37–39 In muscle injury, they promote tissue regeneration through the expression of a proregenerative protein, amphiregulin40 |
CD161+ Tregs are enriched in patients with inflammatory bowel disease (Crohn's disease), suppress inflammation, and accelerate wound closure in the colon41 |
| CD4+ helper T cells | CD4+ T helper cells mediate immune response through cytokine secretion.1 Three types of CD4+ helper cells include the following: TH1 cells, which dominantly secrete interferon (IFN) and tumor necrosis factor (TNF) TH2 cells, which secrete IL-4, IL-5, and IL-13 TH17 cells, which secrete IL-17, IL-21, and IL-22 and follicular helper T cells TH2 CD4+ cells are IL-4-producing T cells that were responsible for enhancing neuronal protection and recovery following CNS injury42,43 |
TH17 cells are found near breast capsule implants and contribute to IL-17a secretion and fibrosis near the breast capsule implant44 TH17 cell frequency and plasma TH17-associated cytokine concentrations positively correlate with carotid artery plaques45 |
| B cells | Secrete IL-10 (intestinal injury)46; Enable skin wound closure through the soluble secretion of IL-6 and transforming growth factor beta47,48 |
In renal transplant patients, B cell-mediated immune regulation was characterized by the ratio of IL-10/TNFα expression Patients with poor graft outcomes had a low IL-10/TNFα ratio in transitional B cells49 |
HLA, human leukocyte antigen; IL, interleukin; NK, natural killer; STAT3, signal transducer and activator of transcription 3; TH2, T helper type 2; Treg, regulatory T cell.