Chemokine Receptor CX3CR1 Mediates Skin Wound Healing by Promoting Macrophage and Fibroblast Accumulation and Function

Abstract

Wounds heal through a highly regulated, self-limited inflammatory response, however, precise inflammatory mediators have not been fully delineated. In this study, we report that in a mouse model of excisional skin wound healing the chemokine CX3CL1 and its receptor CX3CR1 were both highly induced at wound sites; CX3CL1 colocalized with macrophages and endothelial cells, whereas CX3CR1 colocalized mainly with macrophages and fibroblasts. Loss of CX3CR1 function delayed wound closure in both CX3CR1 knockout (KO) mice and in wild-type mice infused with anti-CX3CR1-neutralizing Ab. Conversely, transfer of bone marrow from donor wild-type mice, but not from donor CX3CR1 KO mice, restored wound healing to normal in CX3CR1 KO-recipient mice. Direct effects of CX3CR1 disruption at the wound site included marked reduction of macrophages and macrophage products, such as TGF-β1 and vascular endothelial growth factor. Consistent with this, we observed reduced α-smooth muscle actin (a marker for myofibroblasts) and collagen deposition in skin from wounded CX3CR1 KO mice, as well as reduced neovascularization. Together, the data support a molecular model of skin wound repair in which CX3CR1 mediates direct recruitment of bone marrow-derived monocytes/macrophages which release profibrotic and angiogenic mediators.

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

“…21,22 In all likelihood, it promotes tissue fibrosis indirectly by increasing the mononuclear cell infiltration and not through the activation of hPSCs. This hypothesis is supported by recent reports: (1) Ishida and colleagues 56 showed that CX3CR1 depletion induced a marked reduction in the number of macrophages and in the release of TGF-b1, and observed reduced a-SMA and Collagen-1 depositions in the skin from wounded CX3CR1 À/À mice. (II) Considering that macrophages activate stellate cells and that suppression of macrophage infiltration inhibits hepatic stellate cell activation and liver fibrosis, the fractalkine/CX3CR1-triggered macrophage tissue infiltration might represent another possible contributor to fibrogenesis in CP.…”

Differential Roles of Macrophages in Diverse Phases of Skin Repair

“…Furthermore, wounds in the neonatal PU.1 null mouse, which lacks macrophages and neutrophils (but also B cells, mast cells, eosinophils), heal without scar and, surprisingly, with a similar time course as wild-type siblings (13). However, the need of macrophages for physiological repair in adults is supported in recent wound healing studies in various murine knockout models in which impaired wound healing is associated with an attenuated number of macrophages at the wound site (14)(15)(16)(17)(18). Although all of these studies emphasize that leukocytes significantly affect the quality of the healing response, knowledge of these models is limited, because they either do not target pathways mediated exclusively by macrophages or they address a neonate repair response, which is known to differ from healing in the adult organism (19).…”

Colony-Stimulating Factor-1 Promotes Kidney Growth and Repair via Alteration of Macrophage Responses

“…3 Embryonic macrophages appear to play a positive trophic role that may have parallel reparative functions in many adult tissues undergoing repair and cellular replacement. 1,20 A number of studies have suggested that infiltrating macrophages along with the trophic factors they release participate in tissue repair of the kidney, 20 -22 brain, 23 skin, 24,25 lung, 26 liver, 27 heart, 28 gastrointestinal tract, 29,30 and skeletal muscle. 31,32 Indeed, the pleiotrophic roles for CSF-1 in reproduction, development of multiple organ systems, and maternal-fetal interactions during pregnancy by macrophage-mediated processes have also been well defined.…”