Toll-like receptor 9 plays a key role in the autonomic cardiac and baroreflex control of arterial pressure

Abstract

The crosstalk between the immune and the autonomic nervous system may impact the cardiovascular function. Toll-like receptors are components of the innate immune system and play developmental and physiological roles. Toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases, such as hypertension and heart failure. Since such diseases are commonly accompanied by autonomic imbalance and lower baroreflex sensitivity, we hypothesized that TLR9 modulates cardiac autonomic and baroreflex control of arterial pressure (AP). Toll-like receptor 9 knockout (TLR9 KO) and wild-type (WT) mice were implanted with catheters into carotid artery and jugular vein and allowed to recover for 3 days. After basal recording of AP, mice received methyl-atropine or propranolol. AP and pulse interval (PI) variability were evaluated in the time and frequency domain (spectral analysis), as well as by multiscale entropy. Spontaneous baroreflex was studied by sequence technique. Behavioral and cardiovascular responses to fear-conditioning stress were also evaluated. AP was similar between groups, but TLR9 KO mice exhibited lower basal heart rate (HR). AP variability was not different, but PI variability was increased in TLR9 KO mice. The total entropy was higher in TLR9 KO mice. Moreover, baroreflex function was found higher in TLR9 KO mice. Atropine-induced tachycardia was increased in TLR9 KO mice, whereas the propranolol-induced bradycardia was similar to WT mice. TLR9 KO mice exhibit increased behavioral and decreased tachycardia responses to fear-conditioning stress. In conclusion, our findings suggest that TLR9 may negatively modulate cardiac vagal tone and baroreflex in mice.

Novel adaptive and innate immunity targets in hypertension

“…TLR9, which recognizes mitochondrial DNA, a product of tissue damage, is also upregulated in the circulation of SHRs, and treatment with TLR9 inhibitory oligodinucleotide ODN2088 resulted in a reduction in systolic blood pressure 58 . This follows with the studies performed by Rodrigues et al in TLR9 −/− mice, implicating TLR9 in the cardiac autonomic and baroreflex control of arterial blood pressure 59 . A previously undiscovered link between TLR2 and NLRP3 in renal tubular epithelial cells was recently revealed, where TLR2 ligands induced NLRP3 inflammasome-dependent necrosis, demonstrating the crosstalk between TLRs and other PRRs in the kidney 60 .…”

Baroreflex control of renal sympathetic nerve activity in early heart failure assessed by the sequence method

“…; Rodrigues et al . ). Thus, the arterial baroreflex can respond to AP changes with concordant changes in cardiac interval in only a few (20%) cases.…”

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

“…Furthermore, TLR9 activation increased blood pressure and induced vascular dysfunction in male normotensive rats and induced maternal hypertension in pregnant rats (Goulopoulou et al, 2012). Moreover, TLR9 has been observed to be a negative regulator of cardiac vagal tone and baroreflex function (Rodrigues et al, 2015).…”