Co-expression of interleukin (IL)-17RA and IL-36 in the hypothalamic paraventricular nucleus of the stress-induced hypertension rats

Objectives: The up-regulation of proinflammatory cytokines in the hypothalamic paraventricular nucleus (PVN) is well demonstrated to be involved in the development of neurogenic hypertension, including stress-induced hypertension (SIH). IL-17A has been found to be increased in the PVN of several hypertensive animal models and has been shown to play a key role in the development of hypertension. Although IL-36 gamma was found to be expressed in spinal neurons, its role in hypertension remains elusive. Here, we investigated the co-expression of IL-17 receptor A (IL-17RA) and IL-36 gamma in the PVN cells of SIH rats. Methods: The electric foot shock combined with buzzer noise stressors were used to make hypertensive rat model. The immunochemical staining or immunofluorescence staining was used to reveal cells as requested. The Western blot was used to detect the related protein levels. Results and Conclusion: In the PVN of the SIH rats, the number of CD3(+)CD4(+) T cells was significantly increased by the immunochemical staining. Additionally, the protein levels of ROR gamma t and IL-17A were significantly upregulated by Western blot, confirming the infiltration of CD4(+) T cells and differentiation into Th17 cells in the PVN of SIH rats. Immunofluorescence staining revealed abundant expression of IL-17RA in PVN neurons, with relatively less expression in astrocytes or microglia. Furthermore, IL-36 gamma positive cells and protein expression of IL-36R were significantly increased. Notably, this study demonstrates for the first time that most IL-36 gamma cells were strongly colocalized with IL-17RA positive cells in the PVN of SIH rats, and the colocalized cells were significantly higher in SIH rats. This suggests that IL-17A secreted by infiltrated Th17 cells may stimulate PVN neurons to produce IL-36 gamma via IL-17RA, indicating that the combination of IL-17 and IL-36 gamma might produce strong pro-inflammatory effects in the PVN of SIH rats.