μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System

Abstract

Opioids, a kind of peptide hormone involved in the development of hypertension, cause systemic and cerebral inflammation, and affects regions of the brain that are important for blood pressure (BP) control. A cause-and-effect relationship exists between hypertension and inflammation; however, the role of blood pressure in cerebral inflammation is not clear. Evidence showed that AT1R and μOR heterodimers’ formation in the NTS might lead to the progression of hypertension. In this study, we investigated the formation of the μOR/AT1R heterodimer, determined its correlation with μORs level in the NTS, and explored the role of TLR4-dependent inflammation in the development of hypertension. Results showed that Ang II increased superoxide and Iba-1 (microgliosis marker: ionized calcium-binding adaptor molecule (1) levels in the NTS of spontaneously hypertensive rats (SHRs). The AT1R II inhibitor, losartan, significantly decreased BP and abolished superoxide, Iba-1, TLR4 expression induced by Ang II. Furthermore, losartan significantly increased nNsOSS1416 phosphorylation. Administration of a μOR agonist or antagonist in the NTS of WKY and SHRs increased endogenous μ-opioids, triggered the formation of μOR/AT1R heterodimers and the TLR4-dependent inflammatory pathway, and attenuated the effect of depressor nitric oxide (NO). These results imply an important link between neurotoxicity and superoxides wherein abnormal increases in NTS endogenous μ-opioids promote the interaction between Ang II and μOR, the binding of Ang II to AT1R, and the activation of microglia. In addition, the interaction between Ang II and μOR enhanced the formation of the AT1R and μOR heterodimers, and inactivated nNOS-derived NO, leading to the development of progressive hypertension.

Unraveling the crosstalk between renin‐angiotensin system receptors

“…39 Consequently, the AT 1 R-μOR heteromer leads to an increase in ADMA levels and a reduction in extracellular regulated kinase 1/2 (ERK1/2) levels, ultimately resulting in a decrease in neuronal NOS-derived nitric oxide (NO) and an elevation in blood pressure. 38 The formation of AT 1 R-μOR heteromers is observed not only in the NTS of SHRs, with higher levels in SHRs compared to normotensive rats, 40 but also in fructose-induced hypertensive rats. 41 The increase in endogenous μopioids in the NTS induces AT 1 R-μOR heteromers, triggering the binding of Ang II to AT 1 R. 40 This leads to microglia and toll-like receptor 4 (TLR-4)-dependent inflammatory pathway activation, resulting in superoxide production and impairment of neuronal NOS in the NTS of both normotensive and hypertensive rats.…”

“…38 The formation of AT 1 R-μOR heteromers is observed not only in the NTS of SHRs, with higher levels in SHRs compared to normotensive rats, 40 but also in fructose-induced hypertensive rats. 41 The increase in endogenous μopioids in the NTS induces AT 1 R-μOR heteromers, triggering the binding of Ang II to AT 1 R. 40 This leads to microglia and toll-like receptor 4 (TLR-4)-dependent inflammatory pathway activation, resulting in superoxide production and impairment of neuronal NOS in the NTS of both normotensive and hypertensive rats. 40 Blockade of AT 1 R abolishes the AT 1 R-induced formation of AT 1 R-μOR heteromers, enhancing the DDAH1-nNOS pathway activity and eliminating superoxide, microgliosis, and TLR-4 expression induced by Ang II.…”

“…41 The increase in endogenous μopioids in the NTS induces AT 1 R-μOR heteromers, triggering the binding of Ang II to AT 1 R. 40 This leads to microglia and toll-like receptor 4 (TLR-4)-dependent inflammatory pathway activation, resulting in superoxide production and impairment of neuronal NOS in the NTS of both normotensive and hypertensive rats. 40 Blockade of AT 1 R abolishes the AT 1 R-induced formation of AT 1 R-μOR heteromers, enhancing the DDAH1-nNOS pathway activity and eliminating superoxide, microgliosis, and TLR-4 expression induced by Ang II. 38,40 Therefore, reducing AT 1 R activation in the NTS through the usage of an AT 1 R antagonist is crucial for impairing the formation of AT 1 R-μOR heteromers and to elicit a depressor response.…”

“…40 Blockade of AT 1 R abolishes the AT 1 R-induced formation of AT 1 R-μOR heteromers, enhancing the DDAH1-nNOS pathway activity and eliminating superoxide, microgliosis, and TLR-4 expression induced by Ang II. 38,40 Therefore, reducing AT 1 R activation in the NTS through the usage of an AT 1 R antagonist is crucial for impairing the formation of AT 1 R-μOR heteromers and to elicit a depressor response. Similar results were reported in the NTS of fructose-induced hypertensive rats, where TLR-4 inhibition disrupted AT 1 R and μOR heteromerization, restoring NO production.…”

Oxidative Stress and Inflammation as Targets for Novel Preventive and Therapeutic Approaches in Non-Communicable Diseases II

“…These findings confirm that p47 phox is a key player in mediating the AngII-induced oxidative stress signaling cascade from the phosphorylation of ASK1, MKK3/6 and MAPKs to the activation of H2AX and p53 and suggest that targeting p47 phox could have great therapeutic potential for preventing or treating AngII-induced cardiac dysfunction and damages. On the other hand, Sun et al [15] demonstrated that an increase in endogenous µ-opioids in the nucleus tractus solitarius (NTS) induces a neurotoxicity cascade with enhanced Ang II binding to the AT1R receptor and activates the microglia which induces superoxide production. Furthermore, they showed how the increase in endogenous µ-opioids induces the formation of µOR/AT1R heterodimers and the TLR4-dependent inflammatory response, which attenuate the nitric oxide (NO)-dependent depressor effect.…”