Pericytes and Adaptive Angioplasticity: The Role of Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)

Abstract

The TNF superfamily member TWEAK has emerged as a pleiotropic cytokine that regulates many cellular functions that include immune/inflammatory activity, angiogenesis, cell proliferation, and fate. TWEAK through its inducible receptor, FGF-inducible molecule 14 (Fn14), can induce both beneficial and deleterious activity that has a profound effect on cell survival. Thus it is highly likely that TWEAK and Fn14 expressed by cells of the neurovascular unit help regulate and maintain vascular and tissue homeostasis. In this chapter we discuss the expression of TWEAK and Fn14 signaling in the cerebral microvascular pericyte. Pericytes are a highly enigmatic population of microvascular cells that are important in regulatory pathways that modulate physiological angiogenesis in response to chronic mild hypoxic stress. A brief introduction will identify the microvascular pericyte. A more detailed discussion of pericyte TWEAK signaling during adaptive angioplasticity will follow.

The TWEAK/Fn14/CD163 axis—implications for metabolic disease

“…Binding of TWEAK to Fn14 recruits cellular inhibitor of apoptosis (cIAP1), TRAF2, TRAF5, and/or TRAF6 into a complex to activate transforming growth factor B-activated kinase 1 (TAK1), NF-κB -inducing kinase (NIK), and mitogen activated protein kinase kinases (MKK) [28]. Activation of TGF-B-activated kinase-1 TAK1 stimulates IB kinase (IKKB) leading to the activation of the early canonical NF-κB pathway characterised by nuclear translocation of RelA [28,29]. NIK phosphorylates and activates IKKB leading to prolonged, but slower, activation of the non-canonical NF-κB pathway symbolised by increased DNA-binding activity of the p52/RelB NF-κB complex [23].…”

CD163 protein inhibits lipopolysaccharide-induced macrophage transformation from M2 to M1 involved in disruption of the TWEAK–Fn14 interaction

“…Additionally, CD163 has been reported to mediate the uptake of TWEAK, leading to the repression of Fn14 activation and the subsequent proinflammatory response [ 17 ]. The binding of TWEAK to Fn14 activates classical and non-classical cascades within the NF-κB pathway [ 54 , 55 ]. Furthermore, the addition of soluble CD163 protein was found to increase the formation of the CD163-TWEAK complex, which may be internalized by macrophages to induce the degradation of TWEAK.…”

Cellular connections, microenvironment and brain angiogenesis in diabetes: Lost communication signals in the post-stroke period

“…Pericytes are multifunctional cells found on pre-capillary arterioles, capillaries, and post-capillary venules (Bonkowski et al, 2011; Dalkara et al, 2011; Dore-Duffy, 2014; Hill et al, 2014; Winkler et al, 2011). They are embedded within the endothelial basement membrane (Attwell et al, 2010; Dalkara et al, 2011).…”

“…It appears that astrocytes and pericytes are both involved in the formation and maintenance of capillary like structures by endothelial cells (Itoh et al, 2011). Studies have also shown that astrocytes are necessary for barriergenesis and directly regulate factors modulating BBB formation, such as tight junction proteins, SSeCKS, Ang-1 and TGFβ (Bonkowski et al, 2011; Dore-Duffy and LaManna, 2007; Dore-Duffy, 2014; Garcia et al, 2004; Lee et al, 2003; Rieckmann and Engelhardt, 2003; Rubin et al, 1991). …”