Inflammation and immunity in organ regeneration

Abstract

The ability of vertebrates to regenerate amputated appendages is increasingly well-understood at the cellular level. Cells mediating an innate immune response and inflammation in the injured tissues are a prominent feature of the limb prior to formation of a regeneration blastema, with macrophage activity necessary for blastema growth and successful development of the new limb. Studies involving either anti-inflammatory or pro-inflammatory agents suggest that the local inflammation produced by injury and its timely resolution are both important for regeneration, with blastema patterning inhibited in the presence of unresolved inflammation. Various experiments with Xenopus larvae at stages where regenerative competence is declining show improved digit formation after treatment with certain immunosuppressive, anti-inflammatory, or antioxidant agents. Similar work with the larval Xenopus tail has implicated adaptive immunity with regenerative competence and suggests a requirement for regulatory T cells in regeneration, which also occurs in many systems of tissue regeneration. Recent analyses of the human nail organ indicate a capacity for local immune tolerance, suggesting roles for adaptive immunity in the capacity for mammalian appendage regeneration. New information and better understanding regarding the neuroendocrine-immune axis in the response to stressors, including amputation, suggest additional approaches useful for investigating effects of the immune system during repair and regeneration.

Learning from regeneration research organisms: The circuitous road to scar free wound healing

“…Damage to the tissue releases mitogens such as Tissue Factor and Tumor Necrosis Factor-alpha (TNF-α) which help to recruit immune cells to the injury site (Eming et al, 2007, 2014, 2017). Additionally, platelets are recruited into the fibrin clot from the vasculature, which then secrete growth factors and chemokines to attract immune cells to the wound bed (Eming et al, 2007, 2014, 2017; LeBert and Huttenlocher, 2014; Mescher et al, 2017; Rosique et al, 2015). Neutrophils arrive to the wound and eliminate microorganisms within the wound bed by phagocytosis and the release of antimicrobial granules (MacLeod and Mansbridge, 2016; Willenborg and Eming, 2014).…”

Mechanisms of urodele limb regeneration

“…The immune system plays an important role in wound repair and regeneration (for reviews see Eming, Wynn, & Martin, 2017; Mescher 2017; Mescher, Neff & King, 2017). Macrophages of the innate immune system are a central mediator of wound repair in mammals.…”

“…Urodeles, which can regenerate limbs as larvae and adults, have a much less developed immune system than anurans (frogs and toads), which regenerate limbs only as early tadpoles, and mammals, which have no limb regenerative power except for digit tips. Macrophages are particularly important for the events of blastema formation during urodele limb regeneration (Godwin & Brockes, 2006; Godwin & Rosenthal, 2014; Mescher, 2017; Mescher et al, 2017; for reviews).…”

Proliferating Cells in Knee Epiphyses of Lizards Allow for Somatic Growth and Regeneration after Damage

“…However, in both lizards and amphibians the damage has to be limited in order to avoid a strong process of inflammation, otherwise cartilage regeneration is impaired and a dense fibrous connective tissue is produced in different proportions with respect the cartilage, resembling the fibrotic process typical for mammals. It is likely that the inflammatory and immune reactions to injury, stronger in mammals than in ectothermic vertebrates, participate in limiting the regeneration of their injured tissues [23][24][25], including the cartilage [39]. Further study on inflammation and chondrogenesis in lizard is required.…”

“…Like during limb regeneration, also the regeneration of the knee in amniotes can be linked to the degree of inflammation produced after a natural traumatic or an experimental intervention, so that a strong immune reaction can adversely affect the entire process of recovery [23][24][25].…”