Rat resistance to rheumatoid arthritis induction as a function of the early‐phase adrenal–pineal crosstalk. (8th December 2022)

• Record Type: Journal Article
• Authors: Córdoba‐Moreno, Marlina O.; Mendes, Mariana Trivilin; Markus, Regina P.; Fernandes, Pedro Augusto
• Is Part Of: Journal of physiology. Volume 601:Number 3(2023)
• Page Start: 535
• Page End: 549
• Publication Date: 2022-12-08
• Subjects: chronic inflammation -- collagen‐induced arthritis -- cytokines -- glucocorticoids -- immune–pineal axis -- melatonin -- rheumatoid arthritis; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP283456
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Abstract: Chronic inflammatory diseases are triggered by causal stimuli that might occur long before the appearance of the symptoms. Increasing evidence suggests that these stimuli are necessary but not always sufficient to induce the diseases. The murine model of type II collagen emulsified in Freund's incomplete adjuvant (collagen‐induced arthritis) to induce rheumatoid arthritis (RA) follows this pattern as some animals do not develop the chronically inflamed phenotype. Considering that in the immune–pineal axis (IPA) theory adrenal–pineal cross‐talk adjusts early phases of inflammatory processes, we investigated whether differences in IPA activation could explain why some animals are resistant (RES) while others develop RA. We observed a similar increase in 6‐sulfatoxymelatonin (aMT6s) excretion from day 3 to 13 in both RES and RA animals, followed by a significant decrease in RA animals. This pattern of aMT6s excretion positively correlated with plasma corticosterone (CORT) in RES animals. Additionally, RA animals presented a lower aMT6s/CORT ratio than saline‐injected or RES animals. Plasmatic levels of tumour necrosis factor were similar in both groups, but interleukin (IL)‐1β and monocyte chemotactic protein 1 (MCP‐1) levels were lower in RES compared to RA animals. IL‐2 and IL‐4 were decreased in RES animals compared to saline‐injected animals. The aMT6s/CORT ratio inversely correlated with the paw thickness and the inflammatory score (levels of IL‐1β, MCP‐1, IL‐2 and IL‐4 combined). Thus, adrenocortical–pineal positive interaction is an early defence mechanism for avoiding inflammatory chronification. Key points: Immune–pineal axis imbalance is observed in early‐phase rheumatoid arthritis development. Only resistant animals present a positive association between adrenal and pineal hormones. The 6‐sulfatoxymelatonin/corticosterone ratio is decreased in animals that develop rheumatoid arthritis. The inflammatory score combining the levels of nocturnal interleukin (IL)‐1β, monocyte chemotactic protein 1, IL‐2 and IL‐4 presents a very strong positive correlation with the size of inflammatory lesion. The 6‐sulfatoxymelatonin/corticosterone ratio presents a strong negative correlation with the inflammatory score and paw oedema size. Abstract : Abstract figure legend Adrenal–pineal crosstalk provides resistance to RA development in rats. Left, resistance: moderately increased CORT levels lead to glucocorticoid receptor stimulation in the pineal gland, counteracting TNF inhibitory effect and potentiating β1 ‐adrenoreceptor‐induced pineal melatonin production. Increased melatonin levels associated with corticosterone reduce cellular migration, regulating an appropriate synovial cellular infiltration and the synthesis of cytokines composing the inflammatory score. Right, rheumatoid arthritis: highly elevated corticosterone levels combined with β1 ‐ + α1 ‐adrenoceptor activation and circulating TNF reduces the synthesis of melatonin by the pineal gland. Lower circulating melatonin levels lead to increased synovial cellular infiltration. Infiltrated cells, resident fibroblasts and resident macrophages produce large amounts of inflammatory factors, leading to chronic inflammation. The data provide evidence that an unbalanced immune–pineal axis activation lies at the point of origin of RA development (Markus et al. 2021). Figure produced with BioRender.com.