Tim Koopmans

β-catenin as a regulator and therapeutic target for asthmatic airway remodeling

Introduction: Pathological alteration in the airway structure, termed as airway remodeling, is a hallmark feature of individuals with asthma and has been described to negatively impact lung function in asthmatics. Recent studies have raised considerable interest in the regulatory role of β-catenin in remodeling asthmatic airways. The WNT/β-catenin signaling pathway is the key to normal lung development and tightly coordinates the maintenance of tissue homeostasis under steady-state conditions. Several studies indicate the crucial role of β-catenin signaling in airway remodeling in asthma and suggest that this pathway may be activated by both the growth factors and mechanical stimuli such as bronchoconstriction. Areas covered: In this review, we discuss recent literature regarding the mechanisms of β-catenin signaling activation and its mechanistic role in asthmatic airway remodeling. Further, we discuss the possibilities of therapeutic targeting of β-catenin. Expert opinion: The aberrant activation of β-catenin signaling by both WNT-dependent and -independent mechanisms in asthmatic airways plays a key role in remodeling the airways, including cell proliferation, differentiation, tissue repair and extracellular matrix production. These findings are interesting from both a mechanistic and therapeutic perspective, as several drug classes have now been described that target β-catenin signaling directly.

Selective targeting of CBP/β-catenin inhibits growth of and extracellular matrix remodelling by airway smooth muscle

Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). β‐catenin, a transcriptional co‐activator, is fundamentally involved in airway smooth muscle growth and may be a potential target in the treatment of airway smooth muscle remodelling.

Selective targeting of CREB‐binding protein/β‐catenin inhibits growth of and extracellular matrix remodelling by airway smooth muscle

Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). β‐catenin, a transcriptional co‐activator, is fundamentally involved in airway smooth muscle growth and may be a potential target in the treatment of airway smooth muscle remodelling.

Cooperative signaling by TGF-β1 and WNT-11 drives sm-α-actin expression in smooth muscle via Rho kinase-actin-MRTF-A signaling

Airway smooth muscle (ASM) remodeling is a key feature in asthma and includes changes in smooth muscle-specific gene and protein expression. Despite this being a major contributor to asthma pathobiology, our understanding of the mechanisms governing ASM remodeling remains poor. Here, we studied the functional interaction between WNT-11 and TGF-β1 in ASM cells. We demonstrate that WNT-11 is preferentially expressed in contractile myocytes and is strongly upregulated following TGF-β1-induced myocyte maturation. Knock-down of WNT-11 attenuated TGF-β1-induced smooth muscle (sm)-α-actin expression in ASM cells. We demonstrate that TGF-β1-induced sm-α-actin expression is mediated by WNT-11 via RhoA activation and subsequent actin cytoskeletal remodeling, as pharmacological inhibition of either Rho kinase by Y27632 or actin remodeling by latrunculin A attenuated sm-α-actin induction. Moreover, we show that TGF-β1 regulates the nuclear expression of myocardin-related transcription factor-A (MRTF-A) in a Rho kinase-dependent fashion, which in turn mediates sm-α-actin expression. Finally, we demonstrate that TGF-β1-induced MRTF-A nuclear translocation is dependent on endogenous WNT-11. The present study thus demonstrates a WNT-11-dependent Rho kinase-actin-MRTF-A signaling axis that regulates the expression of sm-α-actin in ASM cells.

On the Dissimilarity of 5′-AMP Induced Hypothermia and Torpor in Mice

Administration of adenosine-5′-monophosphate (5′-AMP) can induce an artificial but endogenously reversible torpor-like state in mice. The dynamics of body temperature and the relation between body temperature and metabolic rate may indicate the (dis)similarity of this artificial torpor-like state to natural torpor in intact animals. We investigated these in C57BL/6J mice by (1) comparing cooling rates during 5′-AMP induced hypothermia to cooling rates during high workload induced torpor, and by (2) estimating the relative contributions of metabolic suppression and passive temperature (Q 10) effects in the 5′-AMP induced hypothermic state. We did the latter by back-extrapolating the relation between body temperature and metabolic rate in hypothermic conditions to the euthermic temperature level, using calculated Q 10-values. The data indicate that (1) cooling rate in 5′-AMP induced hypothermia is about 1.8 times faster than in natural torpor in workload conditions, and that (2) Q 10 effects can entirely explain the metabolic reduction of 5′-AMP induced hypothermia, indicating that active metabolic suppression may be lacking. Together, this suggests fundamental differences between 5′-AMP induced hypothermia and natural torpor, limiting the validity of the paradigm to the study of effects of hypothermic conditions and temperature related metabolic effects.

Regulation of actin dynamics by WNT-5A: implications for human airway smooth muscle contraction

A defining feature of asthma is airway hyperresponsiveness (AHR), which underlies the exaggerated bronchoconstriction response of asthmatics. The role of the airway smooth muscle (ASM) in AHR has garnered increasing interest over the years, but how asthmatic ASM differs from healthy ASM is still an active topic of debate. WNT-5A is increasingly expressed in asthmatic ASM and has been linked with Th2-high asthma. Due to its link with calcium and cytoskeletal remodelling, we propose that WNT-5A may modulate ASM contractility. We demonstrated that WNT-5A can increase maximum isometric tension in bovine tracheal smooth muscle strips. In addition, we show that WNT-5A is preferentially expressed in contractile human airway myocytes compared to proliferative cells, suggesting an active role in maintaining contractility. Furthermore, WNT-5A treatment drives actin polymerisation, but has no effect on intracellular calcium flux. Next, we demonstrated that WNT-5A directly regulates TGF-β1-induced expression of α-SMA via ROCK-mediated actin polymerization. These findings suggest that WNT-5A modulates fundamental mechanisms that affect ASM contraction and thus may be of relevance for AHR in asthma.

β-Catenin Directs Nuclear Factor-κB p65 Output via CREB-Binding Protein/p300 in Human Airway Smooth Muscle

β-Catenin is a multifunctional protein that apart from its role in proliferative and differentiation events, also acts upon inflammatory processes, mainly via interaction with nuclear factor-κB (NF-κB). However, there is still controversy as to whether β-catenin facilitates or represses NF-κB output. Insights into the molecular mechanisms underlying the interaction between β-catenin and NF-κB have highlighted the cofactors CREB-binding protein (CBP) and p300 as important candidates. Here, we hypothesized that the interaction of β-catenin with CBP/p300 directs NF-κB output. Using human airway smooth muscle (ASM) cells, we found that β-catenin is essential in interleukin -1β (IL-1β)-mediated expression of interleukin-6 (IL-6) by promoting nuclear translocation of the p65 subunit of NF-κB. These effects were independent from WNT pathway activation or other factors that promote β-catenin signaling. In the nucleus, inhibition of either the CBP- or p300-β-catenin interaction could regulate NF-κB output, by enhancing (CBP inhibition) or inhibiting (p300 inhibition) IL-1β-induced expression of IL-6, respectively. Acetylation of p65 by p300 likely underlies these events, as inhibition of the p300-β-catenin interaction diminished levels of acetylated p65 at lysine 310, thereby reducing p65 transcriptional activity. In conclusion, β-catenin is a critical component of NF-κB-mediated inflammation in human ASM, affecting transcriptional output by interacting with the nuclear cofactors CBP and p300. Targeting β-catenin may be an alternative strategy to treat airway inflammation in patients with airway disease, such as asthma.

Revisiting asthma therapeutics: focus on WNT signal transduction

Asthma is a complex disease of the airways that develops as a consequence of both genetic and environmental factors. This interaction has highlighted genes important in early life, particularly those that control lung development, such as the Wingless/Integrase-1 (WNT) signalling pathway. Although aberrant WNT signalling is involved with an array of human conditions, it has received little attention within the context of asthma. Yet it is highly relevant, driving events involved with inflammation, airway remodelling, and airway hyper-responsiveness (AHR). In this review, we revisit asthma therapeutics by examining whether WNT signalling is a valid therapeutic target for asthma.

Selective targeting of CREB-binding protein/β-catenin inhibits growth of and extracellular matrix remodelling by airway smooth muscle: ICG-001 inhibits airway smooth muscle remodelling

Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). β‐catenin, a transcriptional co‐activator, is fundamentally involved in airway smooth muscle growth and may be a potential target in the treatment of airway smooth muscle remodelling.