Systemic sclerosis (SSc)/scleroderma, is the prototypic fibrotic disease causing skin and internal organ fibrosis. Lung fibrosis progression as a patient ages is the leading cause of SSc-related deaths. It is likely that a common effector cell drives fibrosis in multiple organs in SSc, and our preliminary data demonstrate that circulating monocytes are recruited to injured tissues where they differentiate into ?monocyte-derived? macrophages. Using a murine model of lung fibrosis, we performed causal genetic experiments and showed that these monocyte-derived tissue macrophages are critical for the fibrosis development. Unbiased transcriptional profiling of flow-sorted monocyte-derived alveolar macrophages in mice during lung fibrosis, and in human alveolar macrophages from lung explants from patients with SSc undergoing transplantation, showed altered signaling through the Wnt/?-catenin pathway. We found that genetic loss-of- function in Wnt/?-catenin signaling in murine lung macrophages did not affect fibrosis severity, but sped the resolution of fibrosis. These findings are reminiscent of those in aged animals in which fibrosis persists much longer after bleomycin administration compared with young mice. Indeed, the persistence of fibrosis after injury is a characteristic feature of human fibrosis in multiple organs. Furthermore, we found age-related changes in Wnt/?-catenin pathway components in transcriptomes generated from flow sorted alveolar macrophages collected over the lifespan of mice (4-24 months). These findings support our hypothesis that a gain of function in Wnt/?-catenin signaling in monocyte-derived macrophages contributes to the age-related susceptibility to persistent fibrosis in multiple organs. We propose to test this hypothesis in two interrelated specific aims.
In Aim 1, we will determine whether genetic gain- or loss-of-function of Wnt/?-catenin signaling in monocyte-derived macrophages cells enhances or prevents the differential susceptibility of aged animals to multiple organ fibrosis.
In Aim 2, we will determine whether a common deregulated Wnt pathway-related gene expression signature is present in tissue macrophages isolated from the lung and skin of patients with SSc compared to healthy control subjects. Our previous work using whole skin biopsies from mice and SSc patients, demonstrated that alterations in the Wnt/?-catenin system are involved with SSc dermal fibrosis. We now propose to capitalize upon our combined expertise in macrophage biology and Wnt/?-catenin signaling to determine their contribution to accelerated SSc dermal and lung fibrosis in the aged. Altogether, this proposal matches a proven investigative team with a compelling hypothesis that stands to transform the way we think about aging-related fibrosis.
Wnt/?-catenin signaling plays a major role in fibrotic diseases such as systemic sclerosis as evidenced by human and animal studies. We propose to capitalize upon the resources of the Northwestern Scleroderma Program and the Northwestern University Divisions of Rheumatology and Pulmonary Medicine to study the precise role of Wnt/?-catenin signaling in tissue macrophages obtained from patients with systemic sclerosis and from animal models of scleroderma. We hypothesize that Wnt/?-catenin signaling in tissue macrophages is a potential therapeutic target for age-related fibrotic disease including systemic sclerosis.
