GDF15, an update of the physiological and pathological roles it plays: a review

Assadi, Artin; Zahabi, Azadeh; Hart, Robert A. de J.

doi:10.1007/s00424-020-02459-1

Cited by 89 publications

(71 citation statements)

References 110 publications

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“…However, the functionality of GDF15 seems to depend on a variety of conditions, including the organism, surrounding tissue, age, and stimuli. Thus, other studies reported that GDF15 seems to have tissue protective effects in heart, liver, kidney and lung by reducing the extent of damage after injury and inflammation following these events [38][39][40][41]. Abulizi et al [42] demonstrated that a lack of GDF15 upregulates the expression of inflammatory cytokines induced by LPS stimulation.…”

Section: Discussionmentioning

confidence: 98%

GDF15 Supports the Inflammatory Response of PdL Fibroblasts Stimulated by P. gingivalis LPS and Concurrent Compression

Stemmler

Symmank

Steinmetz

et al. 2021

IJMS

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Periodontitis is characterized by bacterially induced inflammatory destruction of periodontal tissue. This also affects fibroblasts of the human periodontal ligaments (HPdLF), which play a coordinating role in force-induced tissue and alveolar bone remodeling. Excessive inflammation in the oral tissues has been observed with simultaneous stimulation by pathogens and mechanical forces. Recently, elevated levels of growth differentiation factor 15 (GDF15), an immuno-modulatory member of the transforming growth factor (TGFB) superfamily, were detected under periodontitis-like conditions and in force-stressed PdL cells. In view of the pleiotropic effects of GDF15 in various tissues, this study aims to investigate the role of GDF15 in P. gingivalis-related inflammation of HPdLF and its effect on the excessive inflammatory response to concurrent compressive stress. To this end, the expression and secretion of cytokines (IL6, IL8, COX2/PGE2, TNFα) and the activation of THP1 monocytic cells were analyzed in GDF15 siRNA-treated HPdLF stimulated with P. gingivalis lipopolysaccharides alone and in combination with compressive force. GDF15 knockdown significantly reduced cytokine levels and THP1 activation in LPS-stimulated HPdLF, which was less pronounced with additional compressive stress. Overall, our data suggest a pro-inflammatory role for GDF15 in periodontal disease and demonstrate that GDF15 partially modulates the force-induced excessive inflammatory response of PdLF under these conditions.

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Section: Discussionmentioning

confidence: 98%

GDF15 Supports the Inflammatory Response of PdL Fibroblasts Stimulated by P. gingivalis LPS and Concurrent Compression

Stemmler

Symmank

Steinmetz

et al. 2021

IJMS

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“…GDF signaling has been previously associated with stimulation of hypertrophic muscle growth and myogenesis by regulating the proliferative and differentiation capacity of muscle stem cells. Overall, they have been characterized as regulators of muscle development, homeostasis, and regeneration ( Varga et al, 2016b ; Kleinert et al, 2018 ; Gil et al, 2019 ; Assadi et al, 2020 ; Borner et al, 2020 ; Breit et al, 2021 ; Laurens et al, 2020 ). Paradoxically, global, potentially maladaptive actions for GDF-15 have also been proposed, such as promotion of atrophy, malaise, and muscle wasting ( Johnen et al, 2007 ; Tsai et al, 2018 ; Patel et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Patsalos

Halász

Medina-Serpas

et al. 2021

Journal of Experimental Medicine

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Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte–derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage–derived factors coordinate tissue repair. Gene expression kinetics–based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration–associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor–expressing macrophages [GFEMs]).

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“…GDF15 is a divergent member of the transforming growth factor-β (TGFβ) superfamily 267 . Physiologically, GDF15 is expressed in multiple tissues at a low concentration, but increases in response to or association with tissue injury, cancer, metabolic disease, CVD and inflammation 267 , 268 . GDF15 has also been proposed to act as an anti-inflammatory cytokine in the infarcted heart 269 .…”

Section: Novel and Emerging Obesity Therapiesmentioning

confidence: 99%