title: Mechanical force prolongs acute inflammation via T-cell-dependent pathways during scar formation.
abstract: Mechanical force significantly modulates both inflammation and fibrosis, yet the fundamental mechanisms that regulate these interactions remain poorly understood. Here we performed microarray analysis to compare gene expression in mechanically loaded wounds vs. unloaded control wounds in an established murine hypertrophic scar (HTS) model. We identified 853 mechanically regulated genes (false discovery rate <2) at d 14 postinjury, a subset of which were enriched for T-cell-regulated pathways. To substantiate the role of T cells in scar mechanotransduction, we applied the HTS model to T-cell-deficient mice and wild-type mice. We found that scar formation in T-cell-deficient mice was reduced by almost 9-fold (P < 0.001) with attenuated epidermal (by 2.6-fold, P < 0.01) and dermal (3.9-fold, P < 0.05) proliferation. Mechanical stimulation was highly associated with sustained T-cell-dependent Th2 cytokine (IL-4 and IL-13) and chemokine (MCP-1) signaling. Further, T-cell-deficient mice failed to recruit systemic inflammatory cells such as macrophages or monocytic fibroblast precursors in response to mechanical loading. These findings indicate that T-cell-regulated fibrogenic pathways are highly mechanoresponsive and suggest that mechanical forces induce a chronic-like inflammatory state through immune-dependent activation of both local and systemic cell populations.
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, 257 Campus Dr., GK-201, Stanford, CA 94305, USA.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Wong
authors.forename: Josemaria
authors.initials: J
authors.lastname: Paterno
authors.forename: Michael
authors.initials: M
authors.lastname: Sorkin
authors.forename: Jason P
authors.initials: JP
authors.lastname: Glotzbach
authors.forename: Kemal
authors.initials: K
authors.lastname: Levi
authors.forename: Michael
authors.initials: M
authors.lastname: Januszyk
authors.forename: Kristine C
authors.initials: KC
authors.lastname: Rustad
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D017439:Cicatrix, Hypertrophic / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D015398:Signal Transduction; D013314:Stress, Mechanical; D013601:T-Lymphocytes / Q000276:immunology*; D014945:Wound Healing / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines