Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cellbased therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening progressive lung disorder with limited therapeutic options. While interleukin-10 (IL-10) is a potent anti-inflammatory and anti-fibrotic cytokine, its utility in treating lung fibrosis has been limited by its short half-life. We describe an innovative hydrogel-based approach to deliver recombinant IL-10 to the lung for the prevention and reversal of pulmonary fibrosis in a mouse model of bleomycin-induced lung injury. Our studies show that a hyaluronan and heparin-based hydrogel system locally delivers IL-10 by capitalizing on the ability of heparin to reversibly bind IL-10 without bleeding or other complications. This formulation is significantly more effective than soluble IL-10 for both preventing and reducing collagen deposition in the lung parenchyma after 7 days of intratracheal administration. The antifibrotic effect of IL-10 in this system is dependent on suppression of TGFβ driven collagen production by lung fibroblasts and myofibroblasts. We conclude that hydrogelbased delivery of IL-10 to the lung is a promising therapy for fibrotic lung disorders.

While tissue injury and repair are known to involve adaptive immunity, the profile of lymphocytes involved and their contribution to dermal scarring remain unclear. We hypothesized that restoration of T cell deficiency attenuates dermal scarring. Approach: We assessed the temporal-spatial distribution of T lymphocytes and their subtypes during the physiological dermal wound repair process in mice. Also, we compared the scarring outcomes between wild-type (WT) and severe combined immunodeficient (SCID) mice, which are lymphocyte deficient. Complementary gain-of-function experiments were performed by adoptively transferring lymphocyte subsets to validate their contribution to tissue repair in wounded SCID mice. Results: CD4 + T lymphocytes were present within dermal wounds of WT mice beginning on day 1 and remained through day 30. Wounds of SCID mice exhibited accelerated closure, increased inflammation, limited neovascularization, and exacerbated scarring compared with WT mice. Conversely, transfer of either mixed B and T lymphocytes or CD4 + lymphocytes alone into SCID mice resulted in moderated healing with less inflammation, collagen deposition, and scarring than control SCID wounds. In contrast, transfer of other lymphocyte subsets, including helper T lymphocytes (CD3 + CD4 + CD25-), CD8 + T cells and B cells, or regulatory T lymphocytes (CD4 + CD25 + CD127 low), did not reduce scar. Innovation: The finding that lymphocytes delay wound healing but reduce scar is novel and provides new insights into how dermal scarring is regulated. Conclusion: Our data support a suppressive role for CD4 + T cells against inflammation and collagen deposition, with protective effects in early-stage dermal wound healing. These data implicate adaptive immunity in the regulation of scarring phenotypes.