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PubMed · 16148944

Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.

Thorsten Peters·Anca Sindrilaru·Boris Hinz·Ralf Hinrichs·André Menke·Ezz Al Din Al-Azzeh·Katrin Holzwarth·Tsvetelina Oreshkova·Honglin Wang·Daniel Kess·Barbara Walzog·Silke Sulyok·Cord Sunderkötter·Wilhelm Friedrich·Meinhard Wlaschek·Thomas Krieg·Karin Scharffetter-Kochanek
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Abstract

We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18(-/-) mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers alpha-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18(-/-) mice, suggesting an impaired myofibroblast differentiation. TGF-beta signalling was clearly involved since TGF-beta1 and TGF-beta receptor type-II protein levels were decreased, while TGF-beta(1) injections into wound margins fully re-established wound closure. Since, in CD18(-/-) mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18(-/-) neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-beta1. Indeed, in neutrophil-macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-beta1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing.

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ActinsAnimalsBlotting, WesternCD18 AntigensCell DifferentiationCell MovementCytokinesFibroblastsFibronectinsImmunohistochemistryLeukocyte-Adhesion Deficiency SyndromeMacrophagesMiceMice, KnockoutNeutrophilsPhagocytosisTransforming Growth Factor betaTransforming Growth Factor beta1Wound HealingComparative StudyJournal ArticleResearch Support, Non-U.S. Gov't

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Thorsten Peters, Anca Sindrilaru, Boris Hinz, Ralf Hinrichs, André Menke, Ezz Al Din Al-Azzeh, Katrin Holzwarth, Tsvetelina Oreshkova, Honglin Wang, Daniel Kess, Barbara Walzog, Silke Sulyok, Cord Sunderkötter, Wilhelm Friedrich, Meinhard Wlaschek, Thomas Krieg, Karin Scharffetter-Kochanek. 2005-09-08. Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.. https://doi.org/10.1038/sj.emboj.7600809

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