title: Artificial extracellular matrices composed of collagen I and high-sulfated hyaluronan promote phenotypic and functional modulation of human pro-inflammatory M1 macrophages.
abstract: The sequential phases of biomaterial integration and wound healing require different macrophage functions mediated by distinct macrophage subsets. During the initial phase of healing, pro-inflammatory M1 macrophages (MΦ1) are required to clear the wound from microbes and debris; however, their unopposed, persistent activation often leads to disturbed integration of biomaterials and perturbed wound healing. Here we investigated whether pro-inflammatory macrophage functions are affected by immunomodulatory biomaterials based on artificial extracellular matrices (aECM). To address this issue, we tested the capacity of two-dimensional aECM consisting of collagen I and hyaluronan or sulfated derivatives of hyaluronan to affect functions of in vitro polarized human pro-inflammatory MΦ1. The aECM containing high-sulfated hyaluronan substantially decreased inflammatory macrophage functions, including pathogen uptake and release of the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-12 due to impaired activation of nuclear factor "kappa-light-chain-enhancer" of activated B-cells. Moreover, these macrophages secreted immunregulatory IL-10 and showed reduced activity of the transcription factors signal transducer and activator of transcription 1 and interferon-regulating factor 5, both controlling macrophage polarization to MΦ1 subsets. Our data reveal that the collagen I matrix containing high-sulfated hyaluronan possesses immunomodulating properties and dampens inflammatory macrophage activities by impeding signaling pathways crucial for polarization of pro-inflammatory MΦ1. We therefore suggest this aECM as a promising coating for biomaterials to modulate inflammatory macrophage functions during the healing response and recommend its further testing as a three-dimensional construct and in in vivo models.
authors.affiliation: Department of Dermatology, Venerology und Allergology, Leipzig University, 04103 Leipzig, Germany. sandra.franz@medizin.uni-leipzig.de
authors.forename: Sandra
authors.initials: S
authors.lastname: Franz
authors.forename: Francie
authors.initials: F
authors.lastname: Allenstein
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kajahn
authors.forename: Inka
authors.initials: I
authors.lastname: Forstreuter
authors.forename: Vera
authors.initials: V
authors.lastname: Hintze
authors.forename: Stephanie
authors.initials: S
authors.lastname: Möller
authors.forename: Jan C
authors.initials: JC
authors.lastname: Simon
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D024042:Collagen Type I / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; C431713:IRF5 protein, human; D018836:Inflammation Mediators; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006820:Hyaluronic Acid