Biology subjects

Giovannone, B.

Publications and source records attributed to Giovannone, B..

3 recordsLinked to original sources

bioRxiv2021

Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis

Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis. We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from SSc patients deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This can be mimicked in healthy fibroblasts stimulated by soluble factors that drive inflammation and fibrosis in SSc and is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling. In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.

immunology↗

bioRxiv2020

Genomic structural variation in Nebbiolo grapevines at the individual, clonal and cultivar levels

Structural Variants (SVs) are a widely unexplored source of genetic variation, both due to methodological limitations and because they are generally associated to deleterious effects. However, with the advent of long-range genomic platforms, it has become easier to directly detect SVs. In the same direction, clonally propagated crops provide a unique opportunity to study SVs, offering a suitable genomic environment for their accumulation in heterozygosis. In particular, it has been reported that SVs generate drastic levels of heterozygosity in grapevines. Nebbiolo (Vitis vinifera L.) is a grapevine cultivar typical of north-western Italy, appreciated for its use in producing high-quality red wines. Here, we aimed to analyze the frequency of SVs in Nebbiolo, at three different organizational levels. For this purpose, we generated genomic data based on long-reads, linked-reads and optical mapping. We assembled a reference genome for this cultivar and compared two different clones, including V. vinifera reference genome (PN40024) in our comparisons. Our results indicate that SVs differentially occurring between Nebbiolo clones might be rare, while SVs differentiating haplotypes of the same individual are as abundant as those that occur differentially between cultivars.

genomics↗

bioRxiv2019

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of monocyte-derived cells

Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in systemic sclerosis, a prototypic inflammatory and fibrotic disease. Here, we integrated 65 paired longitudinal transcriptional and methylation profiles from monocyte-derived cells with/without CXCL4 exposure. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters the trajectory of monocyte differentiation, inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key transcriptional regulators including CIITA. CXCL4 exposed monocyte-derived cells directly trigger a fibrotic cascade by producing ECM molecules and inducing myofibroblast differentiation. Inhibition of CIITA mimicked CXCL4 in inducing a pro-inflammatory and pro-fibrotic phenotype, validating the relevance of the gene regulatory network. Our study unveils CXCL4 as a key secreted factor driving innate immune training and forming the long-sought link between inflammation and fibrosis.

bioinformatics↗