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bioRxiv · 10.1101/2021.05.11.443647

Myeloid-mediated IL-1R signaling in immuno-responsive Thy-1 negative fibroblasts is critical for pulmonary fibrosis

Abebayehu, D.·Yeh, C.-R.·Bingham, G. C.·Ewald, S. E.·Barker, T. H.
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with poorly defined pathogenic mechanism and no cure. It is characterized by chronic inflammation, myofibroblast accumulation, and aberrant extracellular matrix (ECM) remodeling. Fibrosis progression is considered to occur due to sustained aberrant fibroblast mechanotransduction: sensing "normal" soft tissue as stiff scarred tissue leading to the overproduction of ECM that then stiffens the microenvironment, thus reinforcing a progressive, stiffness-dependent fibrotic program. How chronic inflammation leads to aberrant mechanotransduction is not well understood. Thy-1 is a regulator of mechanotransduction in fibroblasts. Thy-1 expression is lost in fibroblastic foci, the active sites of fibrosis, although the mechanism of this loss is unknown. We demonstrate that in IPF tissue, the SMA+ fibroproliferative foci express the Type 1 IL-1 receptor (IL-1RI) and IL-1RI-deficient mice did not develop bleomycin-induced pulmonary fibrosis. Using ASC speck formation during inflammasome activation as a marker of mature IL-1{beta} release, we identified the immune compartment as the source of active IL-1{beta} during bleomycin-induced fibrosis. Furthermore, incubating mouse lung fibroblasts on soft (2kPa) hydrogels with IL-1{beta} was sufficient to reduce Thy-1 surface expression and induce v{beta}3 integrin activation. As expected, Thy-1 negative fibroblasts exhibited elevated v{beta}3 integrin activation but surprisingly, Thy-1 negative fibroblasts also expressed higher levels of IL-1RI, potentially linking the immuno-responsive and mechanosensitivity of this fibroblast subpopulation. Leveraging the non-resolving fibrosis that occurs in Thy-1-/- mice, we observed that crossing Thy-1-/- mice onto the IL-1RI-/- background was sufficient to reduce fibrosis. Together, these data indicate that Thy-1 negative fibroblasts are an immuno-responsive subpopulation that also display altered mechanotransduction, potentially serving as the link between the noted inflammation and aberrant mechanotransduction observed in IPF.

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Abebayehu, D., Yeh, C.-R., Bingham, G. C., Ewald, S. E., Barker, T. H.. 2021-05-11. Myeloid-mediated IL-1R signaling in immuno-responsive Thy-1 negative fibroblasts is critical for pulmonary fibrosis. https://doi.org/10.1101/2021.05.11.443647

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