Introduction

Autoimmune diseases are a group of multifactorial disorders with complex and unclear etiology. Autoimmune rheumatic diseases are characterized by similar pathophysiological mechanisms and risk of systemic complications such as cardiovascular diseases, osteoporosis, and early death [1, 2]. Clinical syndromes are initiated by an abnormal immune response that incorrectly reads self antigens as foreign, attacking the body and leading to inflammation.

The immune system produces autoantibodies directed against self antigens. This process, called autoimmunity, is the basis for autoimmune diseases [3]. To date, two ways of autoimmunity development are known. Firstly, physiological autoimmunization may be characterized by a lack of clinical symptoms, i.e., the production of autoantibodies, and at this point the body’s homeostasis is maintained by elimination of degraded self and non-self antigens. The second process is associated with the occurrence of pathological autoimmune reactions that causes tissue damage. The occurrence of genetic predisposition and/or environmental factors (e.g., smoking, UV light, heavy metals) with increased activation of autoreactive T and B lymphocytes leads to tissue damage and loss of their functions [4, 3].

The occurrence of inflammation results from a complex relationship between genetics, hormonal, epigenetics, and environmental factors [1]. The association between the severity of rheumatoid arthritis and the expression of the major histocompatibility complex (MHC), known in humans as human leukocyte antigens (HLA), has been described. The HLA alleles that predispose to the disease, in addition to HLA alleles protecting against autoimmune diseases, are present [5].

Hypothalamic-pituitary-adrenal (HPA) immune axis dysfunction could participate in autoimmune arthritis pathogenesis. During increased inflammation, there is not enough cortisol produced by the adrenal glands axis [6]. The pathomechanism of environmental factors, smoking [7], obesity [8], malnutrition with vitamin D deficiency, and environmental toxins such as heavy metals, infections, and drugs, on the occurrence of RA remains unclear [9, 8, 10]. Epigenetic disorders, related to changes in gene expression, may result from the environmental impact on humans. The epigenome is sensitive to environmental factors. Lowering of DNA methylation in T cells and peripheral blood mononuclear cells (PBMCs) or modification of histone proteins, described in detail by Araki and Mimura [11], may influence modifications of genes responsible for induction and maintenance of inflammatory processes in joints [12,13,98], and is produced by Th17 [56] and Th22 cells. The production of IL-22 is promoted by IL-17, IL-23, IL-1β, aryl-hydrocarbon receptors (AhR), and Notch signaling [99]. The IL-22R is a complex of IL-22R1 and IL-10R2 containing an intracellular, transmembrane, and extracellular signaling region. The cytokine binds to IL-22R1 leading to the formation of a complex. The IL-22/IL-22R1 complex changes conformation and allows association of IL-10R2, initiating the activation of tyrosine kinases 2 (TYK2) and JAK1, followed by phosphorylation of STAT3 on the tyrosine and serine residues, STAT1 and STAT5. It is also an activator of the MAPK pathways (ERK1/2, MEK1/2, c-Jun N-terminal kinase (JNK), and p38 kinase), which ultimately leads to antibacterial and inflammatory processes as well as tissue repair, depending on the environment in the organism in which the cytokine is expressed [100]. There is data on the duality of IL-22 activity in the literature which show the pro-inflammatory role of IL-22. On the other hand, there is also data on the protective role of IL-22 in controlling lung epithelial damage [101] or intestinal inflammation.

IL-22 levels are elevated in patients with rheumatoid arthritis and there is a relationship between its level and radiographic progression and disease activity [102, 103]. Researchers have shown that sulforaphane has an effect on increasing the levels of ROS in whole blood lymphocytes in RA patients. At the same time, reduced production of pro-inflammatory cytokines, i.e., IL-17A, IL-17F, and IL-22, has been demonstrated [69]. Studies conducted by Liu et al. [104] have shown that norepinephrine (NE), a neurotransmitter released from sympathetic nerves, inhibits the differentiation and function of Th17 cells by activating the β2-adrenergic receptor (β2-AR) on CD4+ T lymphocytes. The studies were conducted on CIA mice. This suggests that NE may have anti-inflammatory effects in CIA. A study was also carried out on rats suffering from pristane induced arthritis (PIA). Increased cytokines produced by Th17 (IL-17A, IL-21, IL-22), mainly IL-22 in the ratio of Th1 cytokines (TNF-α, INF-γ) and Th2 (IL-4, IL-10, TGFβ), have been shown in organs of immune rats (inguinal lymph nodes, spleen). Expression of IL-22 in synovium and serum correlated with the severity of PIA. The concentration of IL-21 was higher in PIA rats but was not significant compared to IL-22. In this study, IL-21 only supported Th17 differentiation and enhanced their response [99]. The same group showed that in PIA rats, the level of IL-22 expression was different in different phases of PIA. IL-22 levels increased in the spleen during the initial and chronic phase and in the synovium in the chronic phase. In contrast, no elevated levels of IL-22 were found in the acute phase of inflammation. In the acute phase, an increase in IL-17F and IFN-γ expression was observed in the synovial membrane of PIA rats [105]. Zhong et al. [106] reports that elevated IL-22+ T cells and IL-22 can promote RA development. Targeting Th22 and Th17 positively influences RA therapy. Patients were divided into two groups after basic treatments using conventional DMARDs, MTX, and leflunomide. The decreased plasma level of IL-22 correlated with a decreased level of Th22 and positively correlated with the reduction of DAS after treatment. The involvement of these cells in the pathogenesis of RA was previously demonstrated [107]. It has also been shown that treatment with MTX or ETA improves sleep efficiency because RA can cause sleep problems with a noted involvement of the HPA axis [108].

Studies were carried out on FLS from RA patients treated with sodium nitroprusside, inducing apoptosis in the presence or absence of IL-22. IL-22 has been shown to increase the viability of RA-FLS and prevent apoptosis. STAT3 inhibitors reversed this process. Studies have shown that IL-22 protects against sodium nitroprusside-induced apoptosis in RA-FLS by activating STAT3 and the Bcl-2 gene [155].