Berberine ameliorates collagen‐induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut

Abstract

Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells.

Berberine delays onset of collagen induced arthritis through T cell suppression

“…In reference to BBR and CIA specifically, prior studies using BBR to ameliorate clinically apparent CIA resulted in a suppression of T h 17 activity alongside the activation/proliferation of T reg , thereby resulting in an increased T reg /T h 17 ratio in BBR treated mice [45,51]. While a study by Yue et al (2017) [46] provides opposing evidence in which BBR did not appear to have significant effect on the frequency of T reg in a CIA model despite seeing amelioration of clinically apparent CIA, their particular model used PBMCs to assess T reg population and FOXP3 expression, as opposed to our study which used splenocytes and draining LN cells. Moreover, animal models of autoimmune diseases other than RA/CIA indicate a protective role for BBR through the increase in T reg population relative to pro-inflammatory cell types.…”

“…BBR has demonstrated the ability to inhibit the production of a variety of proinflammatory cytokines by various immune cells [41,42], having a strong anti-inflammatory effect. It has also been shown to successfully and strongly regulate the inflammatory responses involved in clinically apparent autoimmune diseases in vivo such as collagen-induced arthritis [43][44][45][46], type I diabetes mellitus [47], UC [48,49], and experimental autoimmune encephalomyelitis [50].…”

“…In regard to RA specifically, BBR has been successful at treating clinically apparent collagen induced arthritis (CIA) in vivo (the rodent model of RA) through a number of suggested mechanisms: such as (1) dendritic cell apoptosis [43], (2) interference with MAPK signaling via inhibition of p-ERK, p-38, and p-JNK [44], (3) attenuation of T h 17 activity via inducing cortistatin in the gut [46], (4) restoration between balance of T reg /T h 17 cells [45], (5) the suppression of Th17 differentiation/proliferation through inhibition of CD169 and RORγt transcription factor, and (6) induction of T reg differentiation through aryl hydrocarbon receptor (AhR) activation [51].…”

Berberine demonstrates anti‐inflammatory properties in Helicobacter pylori‐infected mice with chronic gastritis by attenuating the Th17 response triggered by the B cell‐activating factor

“…It has been reported that BAFF is also a crucial cytokine for the generation and expansion of Th17 cells. 30,31 demonstrated that the expression of BAFF is highly represented in the gastric mucosa of H. pylori + patients and that H. pylori has a key role in inducing BAFF secretion by macrophages via regulating the cAMP/PKA/CREB pathway. We found that BAFF expression is high in the gastric mucosa of mice with chronic gastritis caused by H. pylori in vivo and in the cultured DCs and CD4 + T cells, the two main cell types that express BAFF, in vitro.…”

Herbal compounds for rheumatoid arthritis: Literatures review and cheminformatics prediction

“…Additionally, the imbalance in the Th17/Treg ratio plays a great role in the development and pathogenesis of RA (Dai et al, ). Celastrol, geniposide, clematichinenoside AR, artesunate, kirenol, pristimerin, cryptotanshinone, kaempferol, baicalin, (−)‐epicatechin‐3‐ O ‐β‐ d ‐allopyranoside, quercetin, berberine, oxymatrine, piperlongumine, periplocoside A, daphnetin, and kinsenoside may suppress RA by restoring the balance of Th17/Treg cells in injured joints (Astry et al, ; Dai et al, ; Hsiao et al, ; Hsiao et al, ; Lin et al, ; Liu et al, ; Lu et al, ; Ma et al, ; Sun et al, ; Tong et al, ; Tu et al, ; Wang et al, ; Wang et al, ; Xiong et al, ; Yang et al, ; Yang, Yang, & Zou, ; Yang, Zhang, et al, ; Yue et al, ).…”