Disruption of mindin exacerbates cardiac hypertrophy and fibrosis

The cytoplasmic adaptor proteins TNF receptor associated factor (TRAF)3 and TRAF6 are important mediators of TLR signaling. We show here for the first time that another TRAF family member, TRAF5, is a negative regulator of TLR signaling. B lymphocytes from TRAF5−/− mice produced more IL-6, IL-12p40, IL-10, TNFα, and IgM than did WT B cells after TLR stimulation. Consistent with these data, exogenous overexpression of TRAF5 in B cells inhibited TLR-mediated cytokine and antibody production. TLR stimulation of TRAF5-deficient B cells did not affect cell survival, proliferation, or NF-κB activation, but resulted in markedly enhanced phosphorylation of the MAP kinases ERK1/2 and JNK. TRAF5 negatively regulated TLR signaling in a cell-specific manner, as TRAF5−/− macrophages and dendritic cells showed less dramatic differences in TLR-mediated cytokine production than B cells. Following TLR stimulation, TRAF5 associated in a complex with the TLR adaptor protein MyD88 and the B cell-specific positive regulator of TLR signaling TAB2. Furthermore, TRAF5 negatively regulated the association of TAB2 with its signaling partner TRAF6 after TLR ligation in B cells. These data provide the first evidence that TRAF5 acts as a negative regulator of TLR signaling.

show abstract

“…1 and 4). This agrees with a recent report in which TRAF5 negatively regulates the ERK1/2 pathway in a model of cardiac hypertrophy (32). …”

Section: Discussionsupporting

confidence: 94%

TRAF5 Negatively Regulates TLR Signaling in B Lymphocytes

Buchta

Bishop

2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…237 Investigations by our laboratory have provided functional evidence that an ECM protein, Mindin, affects Ang II-or chronic pressure overload-induced cardiac hypertrophy. 238,239 In human failing hearts, the expression of Mindin is significantly decreased when compared with that in healthy controls. Because of the enhanced activation of AKT/GSK3β and TGF-β1/Smad signaling, cardiac remodeling induced by neuroendocrine factors or an illdefined mechanical stretch was dramatically exacerbated in Mindin-KO mice.…”

Section: Upstream Irf Signaling In Cardiac Remodelingmentioning

confidence: 99%

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

Zhang

2015

Hypertension

Self Cite

View full text Add to dashboard Cite

“…In this issue, Bian and colleagues [8] report on the role of mindin in cardiac hypertrophy. They relied on the mindin gene-deleted mouse model.…”

mentioning

confidence: 99%

“…The authors induced cardiac hypertrophy by thoracic aortic banding or angiotensin II (Ang II) infusion in mindin gene-deleted and wild-type mice. Bian et al found that mindin genedeleted mice were more susceptible to cardiac hypertrophy and fibrosis in response to thoracic aortic banding or Ang II stimulation than wild-type mice [8]. The mindin-deleted mice also had worsened cardiac function during both systole and diastole, compared to wild-type mice.…”

mentioning

confidence: 99%

“…The authors claim that by blocking AKT/GSK3β signaling pharmacologically, the cardiac abnormalities in mindin gene-deleted mice were reversed. Bian et al [8] suggest that mindin is an intrinsic cardioprotective factor that prevents maladaptive remodeling and the transition to heart failure by blocking AKT/GSK3β signaling. How are we supposed to put all this information together?…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mindin your own business

Luft

2012

J Mol Med

View full text Add to dashboard Cite

The extracellular matrix (ECM) consists of a complex glycoprotein assortment and proteoglycan networks that are produced locally by cells in the matrix and are assembled into an organized meshwork, composing the interstitial matrix and the basement membrane. The ECM serves not only as a structural support scaffold for tissues but also regulates cell behavior. Interactions between cells and ECM components influence cell migration, adhesion, differentiation, and proliferation. Inflammatory cell recruitment is mediated by interactions between integrins and several ECM proteins, including fibronectin, vitronectin, and laminin, which function as integrin ligands. Mindin is an F-spondin (FS) family member, multidomain ECM protein, with numerous functions. The FS domain resides at the N-terminus, while the C-terminus features a thrombospondin type 1 repeat. Li and colleagues [1] demonstrated that the FS domain mediates integrin binding and identified the binding site by mutagenesis. Li et al. further showed that mindin recognizes lipopolysaccharide through the thrombospondin repeat domain, and presented evidence that C-mannosylation of this domain influences lipopolysaccharide binding [1]. These complex interactions raised the possibility that mindin could promote activation of both adaptive and innate immune responses. Tan and Lawler [2] investigated the crystal structure of the FS domain and found that the FS domain may be responsible for membrane targeting that could explain mindin's regulation of axonal development. Indeed, mindin and other FS members were shown to promote the outgrowth and adhesion of embryonic hippocampal neurons [3].Mice lacking mindin have an impaired ability to clear bacterial infections, and mindin-deficient macrophages show defective responses to microbial stimuli [4,5]. Mindin binds directly to bacteria and their components and functions as an opsonin for macrophage phagocytosis. Thus, mindin represents a unique pattern recognition molecule in the ECM, as shown in Fig. 1A. Mindin-deficient mice also displayed severely impaired recruitment of neutrophils and macrophages to inflammation sites. Mindin-integrin interactions were also found to have a key function in T cell priming by dendritic cells. The mindin-deficient mice had defective humoral immune responses to T celldependent antigens. The dendritic cells from mindindeficient mice exhibited an impaired capacity to prime CD4+ T cells due to inefficient engagement of T lymphocytes. With this broad role in innate and acquired immunity, it comes as no surprise that mindin has turned in numerous disease processes. For instance, mindin was found in podocytes in a rodent model of diabetic nephropathy [6]. Mindin was also found to modify airway responses in response to noxious agents [7], and now, mindin turns up as an important ECM protein in the heart.In this issue, Bian and colleagues [8] report on the role of mindin in cardiac hypertrophy. They relied on the mindin gene-deleted mouse model. The authors induced cardiac hypertrophy by thoracic ...

show abstract

Disruption of mindin exacerbates cardiac hypertrophy and fibrosis

Cited by 30 publications

References 28 publications

TRAF5 Negatively Regulates TLR Signaling in B Lymphocytes

TRAF5 Negatively Regulates TLR Signaling in B Lymphocytes

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

Mindin your own business

Contact Info

Product

Resources

About