Role of a novel immune modulating DDR2-expressing population in silica-induced pulmonary fibrosis

Abstract

Micro-injuries associated with chronic inhaled particle exposures are linked with activation of the immune response and are thought to contribute to progression of fibrotic disease. In the pulmonary environment, we have previously demonstrated a heterogeneous population of circulating fibroblast precursors (CFPs), which are defined by expression of the pan-leukocyte marker CD45 and the collagen receptor, discoidin domain receptor-2 (DDR2). This population is derived from the hematopoietic stem cell, expresses collagen, and has a fibroblastic morphology in vitro. Herein, we demonstrate a novel subset of CFPs expressing immune markers CD11b, CD11c, and major histocompatibility complex II (MHC II). The CFP population was skewed toward this immune marker expressing subset in animals with silica-induced pulmonary fibrosis. Data indicate that this CFP subset upregulates co-stimulatory molecules and MHC II expression in response to silica-induced fibrosis in vivo. Functionally, this population was shown to promote T cell skewing away from a Th1 response and toward a pro-inflammatory profile. These studies represent the first direct flow cytometric and functional evaluation of the novel immune marker expressing CFP subset in an exposure-induced model of pulmonary fibrosis. Elucidating the role of this CFP subset may enhance our understanding of the complex immune balance critical to mediating exposures at the pulmonary-host interface and may be a valuable target for the treatment of exposure-induced pulmonary fibrosis.

High-Fat Diet Alters Immunogenic Properties of Circulating and Adipose Tissue-Associated Myeloid-Derived CD45+DDR2+ Cells

“…Previous studies in our lab have shown that myeloid-derived CD45 + DDR2 + cells home to pathological environments, where they differentiate into fibroblasts and other stromal subsets [ 48 , 50 ]. Recently, myeloid-derived CD45 + DDR2 + cells were also shown to express markers of immune activation, including CD80 and MHC II, in an inflammatory lung model [ 49 ]. These findings led us to examine if a subset of CD45 + DDR2 + cells contributes to inflammation in the adipose tissue of preobese mice.…”

“…Previously, we showed that a subset of activated CD45 + DDR2 + cell shaves the capacity to skew CD4 + T cells towards a Th17 phenotype [ 49 ]. To determine if adipose tissue from HFD-fed mice triggers CD45 + DDR2 + cells to stimulate T cell cytokine production, sorted CD45 + DDR2 + cells from peripheral blood of control, ND-fed mice were primed in media conditioned by MGAT from HFD- or ND-fed mice and then cultured with CD4 + T cells from control, ND-fed mice.…”

“…This suggests that DDR2 expression on a subset of myeloid-derived immune cells may play a role in activation and inflammatory cytokine production in these cells. Our previous work in a mouse model of silica-induced pulmonary fibrosis showed that a subset of myeloid-derived CD45 + DDR2 + cells honed to lung tissue, expressed markers of immune activation, and were capable of skewing T cell cytokine production [ 49 ]. These prior studies suggest that myeloid-derived CD45 + DDR2 + cells play a role in modulating the immune response and led us to evaluate their role in promoting inflammation in the preobese adipose tissue environment.…”

“…While the fibroblastic phenotype of these cells has been studied, considerably less is known about the immunogenic potential of these cells. Recently, we showed that myeloid-derived CD45 + DDR2 + cells isolated from lung tissue of mice with pulmonary fibrosis expressed high levels of CD80 and MHC II and were capable of stimulating an inflammatory T cell cytokine response [ 49 ]. This suggests that a subset of myeloid-derived CD45 + DDR2 + cells may play a role in regulating the immune response in inflammatory tissue.…”

Longitudinal micro-computed tomography-derived biomarkers quantify non-resolving lung fibrosis in a silicosis mouse model

“…This model suffers from a high mortality rate and variability, is prone to survival bias and is claimed to be self-limiting in time 26 . The short timespan over which fibrosis develops and peaks does not allow truly therapeutic testing of interventions with antifibrotic potential, warranting gearing up to alternative, chronic models where fibrosis does not spontaneously resolve, such as irradiation-induced lung fibrosis 27,28 , transgenic mice and silicosis 29 . Silica instillation leads to fibrotic nodules that resemble those seen in patients exposed to environmental triggers such as dust and particulates 6 .…”