Published Papers (3 Papers)
Open Access
Review
22 May 2025
Systemic
sclerosis (SSc) is an autoimmune disease characterized by widespread fibrosis affecting
multiple organ systems. There is clinical heterogeneity among patients with SSc
in terms of the organs affected. However, the pathophysiology of the disease remains
elusive. The NLRP3 inflammasome is upregulated in SSc and exerts its fibrotic effects
through activation of caspase-1, which in turn activates a fibrotic signaling cascade,
resulting in increased collagen deposition and myofibroblast transition. Recently,
IL-11 has been shown to be elevated in disease and has been shown to participate
in downstream signaling via the NLRP3 inflammasome. A significant number of patients
with SSc will develop pulmonary involvement, termed interstitial lung disease (SSc-ILD).
Though this type of pulmonary involvement is distinct from other types of pulmonary
fibrosis (such as idiopathic pulmonary fibrosis), it may be a valuable model to
study mechanisms of fibrosis that could apply to other fibrotic diseases. Here,
we discuss recent advances in understanding the mechanisms of the NLRP3 inflammasome
and IL-11 in SSc pulmonary fibroblasts. We tie together some of the recent findings,
such as senescence, the unfolded protein response, and reactive oxygen species,
that contribute to fibrotic pathology via modulating NLRP3 activation, possibly
leading to IL-11 expression.
Caya M.McFalls*
Carol M.Artlett
Fibrosis
2025,
3
(2), 10006;
Open Access
Review
27 June 2025
Fibrotic diseases are
driven by the excessive accumulation of extracellular matrix (ECM),
particularly collagens, leading to progressive tissue stiffness and organ
dysfunction. While many factors contribute to fibrosis—including cytokine signaling, integrin-mediated
mechanotransduction, and altered ECM degradation—the synthesis and secretion of collagen remain
central bottlenecks. Collagen biosynthesis is a complex process involving extensive post-translational
modification and intracellular trafficking. The export of procollagen from the
endoplasmic reticulum (ER) requires Transport and Golgi Organisation 1
(TANGO1), a transmembrane organizer of ER exit sites that coordinates cargo
selection, membrane remodeling, and connectivity between the ER and the ER-Golgi-Intermediate-Comaprtment
(ERGIC). By assembling into ring-like structures at ER exit sites, TANGO1
builds a secretory route for bulky cargoes that bypasses conventional vesicle
constraints. Loss of TANGO1 disrupts collagen secretion and causes
developmental defects across various species. In fibrotic tissues, TANGO1 expression
is upregulated, linking secretory machinery to pathological matrix deposition.
Recent work has identified specific interfaces within the complex of TANGO1
with its vertebrate paralogue Cutaneous T-cell lymphoma-associated antigen 5 (cTAGE5)
as targets for cell-permeant peptide inhibitors. Inhibitors that selectively
and specifically block TANGO1 complex formation reduce collagen secretion in
fibroblasts and scar formation in vivo, offering a new strategy to modulate
fibrotic processes.
Olivia Tribillac
Anna Bornikoel
Julian Nüchel
Ines Neundorf
Gerhard Sengle
Beate Eckes
Ishier Raote*
Thomas Krieg*
Fibrosis
2025,
3
(2), 10008;
Open Access
Review
27 June 2025
Fibroblast migration is a critical factor in wound healing, but also plays a fundamental role in fibrosis. For a fibroblast to migrate, the cell must be able to assemble factors that help it crawl across the extracellular matrix. Most of this movement is facilitated through the assembly and stability of the cytoskeleton that connects focal adhesion engagement with the extracellular matrix to intracellular stress fibers that wrap around the nucleus. These intracellular stress fibers help to polarize the fibroblast and orient the nucleus in the direction it is traveling. Changes in intracellular signaling for the fibroblast to move are also required, and this is necessitated by downstream signaling mediated by sonic hedgehog, WNT/β-catenin, ROCK/Rho, and PI3K/AKT. These changes regulate the stability of the cytoskeleton and, in addition, increase the expression of genes involved in cell migration. This review assimilates what is known about the function of the cytoskeleton in migration and the role of intracellular signaling pathways in fibrosis.
Betty T.Jackson
Carol M.Artlett*
Fibrosis
2025,
3
(2), 10009;
