No abstract

Eosinophils, best known for their role in anti-parasitic responses, have recently been shown to actively participate in tissue homeostasis and repair. Their regulation must be tightly controlled, as their absence or hyperplasia is associated with chronic disease (e.g. asthma or inflammatory bowel disease). In the context of skeletal muscle, eosinophils play a supportive role after acute damage. Indeed, their depletion leads to strong defects in skeletal muscle regeneration and, in the absence of eosinophil-secreted interleukin (IL) 4 and IL13, fibro-adipogenic progenitors fail to support muscle stem cell proliferation. However, the role of eosinophils in muscular dystrophy remains elusive. Although it has been shown that eosinophils are present in higher numbers in muscles from mdx mice (a mouse model for Duchenne muscular dystrophy), their depletion does not affect muscle histopathology at an early age. Here, we evaluated the impact of hyper-eosinophilia on the development of fibrofatty infiltration in aged mdx mice and found that muscle eosinophilia leads to defects in muscle homeostasis, regeneration and repair, and eventually hastens death.

AimFibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signallings regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors.MethodWe performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under the Collagen1a1 promotor. We first confirmed that the EGFP was expressed in response to TGFβ1 stimulation in vitro. Then we treated cells with TGFβ1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were tested in vivo in the mice model for the Duchenne muscular dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size).Key findingsFrom the in vitro drug screening, we identified 21 drugs and tested 3 in vivo on the mdx mice. None of the three drugs significantly improved muscle histopathology.SignificanceThe in vitro drug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.

The ability of mesenchymal stromal cells to modulate inflammation is at the basis of the ongoing interest in their therapeutic potential. Yet, reliable success in clinical trials is limited, possibly due to a limited understanding of their impact on the inflammatory milieu in physiological conditions. Here we show that, at steady state, mesenchymal progenitors regulate the balance between type 1 and type 2 inflammatory milieus by acting on innate immune cells through the TAK1-NFkB pathway. Suppressing the constitutive activity of this pathway in MPs leads to skewing of the immune system toward systemic Type 2 inflammation (Th2). These changes have significant effects on diseases with an important inflammatory component, leading to a worsening of disease in a preclinical model of Th2-dependent Asthma, and a reduction of symptoms associated with Th1/Th17-dependent experimental autoimmune encephalitis.