Neuronal guidance proteins in cardiovascular inflammation

Abstract

Cardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

Alternative adenosine Receptor activation: The netrin-Adora2b link

“…Finally, some studies have implicated netrin-1 signaling via the Adora2b in the treatment of Aspergillus fumigatus infection of the cornea (Zhou et al, 2019). Taken together, these studies during inflammation or ischemia and reperfusion provide evidence for the netrin-Adora2b link in attenuating inflammation, promoting the resolution of inflammation and rescuing organ function (Aherne et al, 2013;Mirakaj and Rosenberger, 2017;Keller et al, 2021).…”

“…The properties and functions on netrin-1 within the CNS as neuronal guidance molecule make it an ideal candidate for also guiding inflammatory cell trafficking events. In fact, several other neuronal guidance molecules (Konig et al, 2012;Mirakaj et al, 2012;Kohler et al, 2013;Kohler et al, 2020) have been implicated in immunomodulation and coordination of inflammatory events or resolution of inflammation (Mirakaj and Rosenberger, 2017;Keller et al, 2021). The unique characteristic of netrin-1 to repulse or abolish the attraction of developing neuronal cells via signaling events through the UNC5b receptor makes it a perfect candidate gene for coordinating inflammatory cell migration (Figure 3).…”

“…This process involves the neuronal guidance molecule netrin-1. Netrin-1 is one of neuronal guidance molecules that are critical for neuronal development by either attracting or repelling developing neurons (Serafini et al, 1994;Serafini et al, 1996;Corset et al, 2000;Mirakaj and Rosenberger, 2017;Keller et al, 2021). Several studies suggest that during inflammatory conditions, netrin-1-elicited organ protection during inflammatory hypoxia is dependent on Adora2b signaling (Rosenberger et al, 2009).…”

PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling

“…However, since the present studies demonstrate immediate signaling effects by treating mice with recombinant netrin, it appears more unlikely that the observed cardioprotection is related to preconditioning or education of myeloid progenitor cells. While the current studies are focused on functional roles of the signaling molecule netrin-1 during myocardial IR injury, other neuronal guidance molecules have been implicated in orchestrating inflammatory endpoints as well ( Keller et al, 2021 ; Mirakaj and Rosenberger, 2017 ). For example, a recent study showed elegantly that RBC-derived semaphorin 7A promotes thromboinflammation in an in situ model of murine myocardial IR injury ( Köhler et al, 2020 ).…”

Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1

“…Netrin-1 was originally described as a neuronal guidance molecule important in brain development (47). However, more recent studies implicate netrin in orchestrating inflammatory events, including myocardial inflammation (48). Moreover, other studies had implicated HIF1A in the transcriptional regulation of netrin-1 during hypoxia, and identified netrin-1 as a classic HIF-target gene (44, 49).…”