Baroreflex activation in conscious rats modulates the joint inflammatory response via sympathetic function

Abstract

The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1β and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation.

Keywords: Baroreflex; Inflammation; Neuroimmunomodulation; Parasympathetic activity; Sympathetic activity.

Fig. 1.

Hemodynamic responses to electrical stimulation of the aortic depressor nerve. Tracing of pulsatile arterial pressure (PAP) [white line represents mean arterial pressure] during 2 min of electrical stimulation of the aortic depressor nerve. (A) Control (CTR; n = 9); (B) splenectomized (SPLENX; n = 5); (C) sympathectomized (SYMPX; n = 8); (D) vagotomized (VAGX; n = 6); (E) adrenalectomized (ADX; n = 4) animals. Bar graphs (F and G) show the mean arterial pressure (MAP) and heart rate (HR). Bars represent mean ± standard error. *p < 0.05 compared to baseline within of each group; ^#p < 0.05 compared to baseline in all other groups (Two-way ANOVA for repeated measures followed by the Tukey’s post hoc test).

Fig. 2.

Electrical activation of the baroreflex attenuated the clinical score of experimental arthritis. Effects of the aortic depressor nerve stimulation (ADNs) or sham stimulation (ADNs – sham) over the inflammatory profile of the femorotibial joint in animals challenged with intra-articular zymosan. (A) Clinical score of the knee joint; (B) articular edema, and (C) neutrophilic infiltration in the synovial tissue. (D) Synovial levels of TNF, (E) IL-1β, (F) IL-6, and (G) IL-10. Zymosan (n = 6); ADN sham (n = 5); ADNs (n = 5). Bars represent means ± standard error. *p < 0.05; **p < 0.01; ***p < 0.001 (One-way ANOVA followed by Tukey’s post hoc test.)

Fig. 3.

The Anti-inflammatory effect of electrical activation of the baroreflex is independent of the spleen, vagus nerve or adrenal glands. Effects of the aortic depressor nerve stimulation (ADNs) over the inflammatory profile of the femorotibial joint after intra-articular administration of zymosan in sham ADNs (sham-ADNs), sham surgery (Shams), splenectomized (SPLENX – upper panels), vagotomized (VAGX – middle panels) or adrenalectomized (ADX – lower panels). Clinical score (A, D and G), articular edema (B, E and H), and neutrophilic infiltration (C, F and I). Bars represent means ± standard error. SPLENX group: sham (n = 6); SPLENX (n = 6); sham-s + ADNs (n = 5); SPLENX + ADNs (n = 5). VAGX group: sham (n = 6); VAGX (n = 6); Sham-s + ADNs (n = 4); VAGX + ADNs (n = 6); ADX group: sham (n = 6); ADX (n = 6); Sham-s + ADNs (n = 5); ADX + ADNs (n = 5). *p < 0.05; ^{$ $, **}p < 0.01; ^{$ $ $, ***}p < 0.001 (Two-way ANOVA for repeated measures followed by Bonferroni’s post hoc test.)

Fig. 4.

The anti-inflammatory effect of electrical activation of the baroreflex depends on the integrity of local sympathetic chain. Effects of the aortic depressor nerve stimulation (ADNs) on the inflammatory profile of the femorotibial joint after intra-articular administration of zymosan in sympathectomized (SYMPX) animals. Clinical score (A and D), articular edema (B and E), and neutrophilic infiltration (C and F) in the contralateral (contra: A, B and C) or ipsilateral (ipsi: D, E and F) knee-joint to the sympathectomy (SYMPX). Zymosan (n = 5); SYMPX (n = 5); ADNs (n = 5); SYMPX + ADNs (n = 8). Bars represent means ± standard error. *p < 0.05; **p < 0.01; ***p < 0.001 (Two-way ANOVA for repeated measures followed by Bonferroni’s post hoc test.)