No energy wasted in the fight against vascular inflammation

This editorial refers to ‘α1AMPK deletion in myelomonocytic cells induces a pro-inflammatory phenotype and enhances angiotensin II-induced vascular dysfunction’ by T. Jansen et al., pp. 1883–1893. While the importance of inflammation in propagating cardiovascular disease is now widely accepted, developing anti-inflammatory therapeutics to ameliorate human atherosclerosis and hypertension will require a detailed understanding of the mechanisms through which dysregulated innate and adaptive immune responses engender vascular dysfunction. Activation of the renin–angiotensin system (RAS), in particular, mediates hypertension, vascular injury, and damage to the heart and kidney through the stimulation of pro-inflammatory signalling cascades such as that regulated by NF-κB.1,2 Accordingly, in experimental models RAS-dependent hypertension and/or target organ damage can be attenuated by various forms of immunosuppression. More recently, mechanistic studies have defined the cell lineages that initiate the pro-inflammatory signals that contribute to vascular injury and dysfunction following RAS activation. Many of these experiments implicate inflammatory pathways directly within the vasculature. For example, nuclear translocation of NF-κB’s p65 subunit directly within vascular endothelial cells precipitates vascular remodelling and hypertension,3 whereas stimulation of the mineralocorticoid receptor (MR) drives vascular dysfunction and inflammation in aging experimental animals.4 Manipulating such pathways locally within the vasculature holds promise for limiting pathogenic vascular remodelling without rendering the host susceptible to risks associated with broad immune suppression. After landmark experiments established a key role for T lymphocytes in mediating vascular dysfunction and hypertension during RAS activation,5 a wide variety of immune cell lineages have been implicated in directing vascular injury or remodelling in this context. B cells, which provide humoral defenses within the adaptive immune system, can exacerbate vascular oxidative stress and hypertension, but likely through mechanisms that require the participation of T cells.5,6 T and B cells undergo specific activation after being presented with processed antigens in the context of an MHC molecule expressed on a myeloid cell, the most potent of which is the dendritic cell. Indeed, following RAS activation, dendritic cells present oxidized isolevuglandins to T cells that have the capacity to transfer the susceptibility to vascular dysfunction and hypertension.7 Conversely, adaptive immune cells can also regulate cardiovascular damage via effects on myeloid cell functions. For example, T regulatory cells modulate apoptosis of tissue-resident neutrophils to alleviate angiotensin (Ang) II-induced cardiac hypertrophy and fibrosis.8 Other myeloid cell lineages can provoke vascular injury without explicitly engaging adaptive immune responses. For example, LysM-expressing monocytes contribute to RAS-mediated hypertension at least in part by precipitating oxidant-dependent endothelial dysfunction.9 Thus, cells populating both the innate and adaptive immune systems can exacerbate vascular dysfunction and remodelling during RAS activation, but targeting circulating cells of the immune system to attenuate the progression of cardiovascular disease could potentially interfere broadly with the organism’s intrinsic defenses against invading microbes. Modulating the functions of innate and adaptive immune cells to combat cardiovascular damage without entailing untoward risks of infection will therefore require precise interventions, particularly as the reactive oxygen species (ROS) generated by immune cells to eradicate microbes are also implicated in mediating vascular injury. One possible approach towards attenuating the pathogenic cardiovascular functions of myeloid cells without compromising host defenses is to exploit the link in these cells between energy metabolism and polarization. In this paradigm, the metabolic state of an immune cell influences its polarization and programming to shape its contribution to the inflammatory response.10 For example, AMP-activated protein kinase (AMPK) in macrophages senses the metabolic stress exerted on the cell by an injurious stimulus and tempers the polarization of the macrophage towards a less inflammatory phenotype, thereby limiting the severity of the innate immune response.11 In this context, the experiments from Jansen et al.12 highlight a mechanism through which AMPK in LysM-expressing myelomonocytic cells protects against vascular oxidative stress in the setting of RAS activation (REF). Using an elegant murine conditional gene targeting strategy, the authors show that deletion of AMPK from myelomonocytic cells exacerbates the level of endothelial dysfunction induced by Ang II via a blood pressure-independent mechanism. The worsened vascular dysfunction accrues from exaggerated Nox2-dependent accumulation of ROS throughout the vascular wall, leading to reduced local bioavailability of the vasodilator, nitric oxide (NO). Infiltrating myeloid cells likely contribute to the ROS elaboration as stimulated macrophages lacking AMPK exhibit an augmented oxidative burst compared with controls in vitro, and increased numbers of Nox2+ macrophages accumulate in the aortic wall of Ang II-treated LysM Cre AMPK knockout mice. Thus, the authors establish an exciting protective function of AMPK in myelomonocytic cells to limit oxidant stress in the vasculature during RAS activation (Figure 1). AMP Kinase in myelomonocytic cells preserves vascular endothelial function during renin–angiotensin system activation. Following an injury stimulus, regulation of cellular energy metabolism by AMP Kinase (AMPK) in LysM-expressing myelomonocytic cells attenuates endothelial dysfunction and vascular inflammation by suppressing expression of the type 1A angiotensin (AT1A) receptor, limiting elaboration of reactive oxygen species, blunting the generation of pro-inflammatory cytokines, and down-regulating surface expression of the myeloid cell chemokine receptor CCR2. Future studies will be helpful to extend and clarify our understanding of AMPK’s functions in myeloid cells. For example, the authors point to elevated iNOS (NOS2) levels in the aortae of the Ang II-treated LysM AMPK knockout animals as evidence of the pro-inflammatory polarization of macrophages infiltrating their vasculature. This finding coupled with the neutral blood pressure phenotype of the knockouts would suggest that the actions of iNOS in hypertension are likely organ- and context-specific as pharmacologic inhibition of iNOS causes blood pressure elevation,13 highlighting the potential anti-hypertensive actions of iNOS. Second, the authors have previously reported that the type 1A Ang II (AT1A) receptor on monocytes is required for a full hypertensive response to Ang II,9 and suggest that, in the current studies, up-regulation of the AT1A receptor contributes to enhanced ROS production by AMPK KO macrophages (REF). This finding is consistent with previous reports of impaired phagocytic capacity AT1A receptor-deficient macrophages.14 However, our own group reported that AT1A receptor stimulation on LysM-expressing myelomonocytic cells actually suppresses their pro-inflammatory polarization without impacting the hypertensive response.15 Nevertheless, AT1A receptor functions on myeloid cells may also be organ- and context-specific as stimulating the AT1A receptor on myeloid cells in the central nervous system is pro-inflammatory and contributes to experimental dementia.16 Collectively, these studies point to the complexity of emerging interactions between the RAS, energy metabolism, and inflammatory polarization in myeloid cells. In sum, Jansen et al. have identified AMPK as an exciting new target in myeloid cells that can limit the extent of vascular oxidant stress and dysfunction in the setting of RAS activation. As RAS blockade reduces blood pressure to some extent in the majority of human patients with essential hypertension, a cell-specific therapy that safely potentiates AMPK signalling within innate immune cells could have broad applicability for hypertensive patients who develop target organ damage. To underpin such translational efforts, additional pre-clinical studies will be required that elucidate bidirectional mechanisms through which cellular metabolism guides immune cell polarization and the converse. As mechanisms of energy allocation are fundamental to a cell’s survival, targeting metabolic pathways within myeloid cells rather than the cytokines they elaborate could have profound effects that cooperate more dynamically with those functions of the immune cells refined by evolution. Accordingly, such a strategy could potentially provide protection from cardiovascular disease without materially compromising immune surveillance from infection or malignancy. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.