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Review
. 2024 Aug 5;16(15):2569.
doi: 10.3390/nu16152569.

Nature of the Association between Rheumatoid Arthritis and Cervical Cancer and Its Potential Therapeutic Implications

Kirill Gusakov  1 , Alexander Kalinkovich  2 , Shai Ashkenazi  1 , Gregory Livshits  1   2
Affiliations
Review

Nature of the Association between Rheumatoid Arthritis and Cervical Cancer and Its Potential Therapeutic Implications

Kirill Gusakov et al. Nutrients. .

Abstract

It is now established that patients with rheumatoid arthritis (RA) have an increased risk of developing cervical cancer (CC) or its precursor, cervical intraepithelial neoplasia (CIN). However, the underlying mechanisms of this association have not been elucidated. RA is characterized by unresolved chronic inflammation. It is suggested that human papillomavirus (HPV) infection in RA patients exacerbates inflammation, increasing the risk of CC. The tumor microenvironment in RA patients with CC is also marked by chronic inflammation, which aggravates the manifestations of both conditions. Gut and vaginal dysbiosis are also considered potential mechanisms that contribute to the chronic inflammation and aggravation of RA and CC manifestations. Numerous clinical and pre-clinical studies have demonstrated the beneficial effects of various nutritional approaches to attenuate chronic inflammation, including polyunsaturated fatty acids and their derivatives, specialized pro-resolving mediators (SPMs), probiotics, prebiotics, and certain diets. We believe that successful resolution of chronic inflammation and correction of dysbiosis, in combination with current anti-RA and anti-CC therapies, is a promising therapeutic approach for RA and CC. This approach could also reduce the risk of CC development in HPV-infected RA patients.

Keywords: HPV-infection; chronic inflammation; dysbiosis; nutrition; specialized pro-resolving mediators.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic presentation of mechanisms underlying the involvement of gut and vaginal dysbiosis in the creation of chronic inflammation in RA patients with HPV-induced CC. Gut and vaginal dysbiosis in RA patients is characterized by the prevalence of specific bacteria species that cause several detrimental effects, such as the destruction of tight junction proteins and intestinal barrier integrity. This results in lipopolysaccharide leakage into the gut lumen, leading to the activation of gut-resident immune cells, including dendritic cells (DCs), macrophages, neutrophils, intraepithelial lymphoid cells (ILCs), Th17 cells, B cells, invariant natural killer T cells (iNKTs), mucosal-associated invariant T cells (MAITs), T-follicular helper cells (Tfhs), and T-regulatory cells (Tregs). The activated immune cells secrete a variety of pro-inflammatory molecules, which can activate epithelial and immune cells in autocrine, paracrine, and endocrine (systematic) manners, culminating in the creation of chronic inflammation. HPV infection is accompanied by both gut and vaginal dysbiosis, typically associated with the prevalence of bacterial species, as displayed in the diagram. Development of CC in HPV-infected RA patients exacerbates gut and vaginal dysbiosis. Dysbiosis, in turn, maintains and worsens chronic inflammation, which, as suggested in the review, is responsible for the aggravation of RA and CC manifestations. Further explanations are given in the text. Abbreviations: CIN, cervical intraepithelial neoplasia; C. rodentium, Citrobacter rodentium; C. aerofaciens, Collinsella aerofaciens; HPV, human papillomavirus; P. gingivalis, Porphyromonas gingivalis; SFB, segmented filamentous bacteria; TME, tumor microenvironment.
Figure 2
Figure 2
A schematic presentation of the chronic inflammatory profile in RA patients with CC. The cells depicted in the diagram are found in both the inflamed joints and the TME of HPV-infected RA patients with CC. They express and secrete a variety of factors, which are mostly pro-inflammatory or immunosuppressive, creating a vicious loop of chronic inflammation. Moreover, infection of RA patients with HPV can further aggravate chronic inflammation and manifestations. It can also contribute to the enhanced progression of CIN to CC. Further explanations are given in the text. Abbreviations: Arg-1, arginase 1; BREG, B regulatory cells; CCL20, chemokine ligand 20; COX, cyclooxygenase; CSF, colony-stimulating factor; CTLA, cytotoxic T lymphocyte-associated protein; DC, dendritic cell; Foxp3, forkhead box P3; GM-CSF, granulocyte-macrophage growth factor; HPV, human papillomavirus; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; LIF, leukemia inhibitory factor; MDSC, myeloid-derived suppressor cells; MMP, metalloproteinase; Mph, macrophage; Nets, netosis; Neu, neutrophil; NK, natural killer cell; NO, nitrogen oxide; PD-L1, programmed death-ligand-1; PGE2, prostaglandin E2; RANKL, receptor activator of NF-kB ligand; RANTES, regulated upon activation, normal T cell expressed and presumably secreted; ROS, reactive oxygen species; TGF, transforming growth factor; Th, T helper cell; TLR, toll-like receptor; TME, tumor microenvironment; TREG, T regulatory cell; VEGF, vascular endothelial growth factor.
Figure 3
Figure 3
Simplified presentation of SPM biosynthesis, SPM receptors, and the process of inflammation resolution. (A) During the resolution phase of acute inflammation, SPMs (e.g., resolvins RvE1, 2, 3; RvD1-6) and maresins (MaR1,2) are biosynthesized from essential ω-3 PUFAs, including EPA and DHA. The main enzymes involved in the production of resolvins and maresins are CYP450 and LOX. There are several intermediates, such as 17/18-HpDHAs in the synthesis of resolvins and 14-HDHA in the synthesis of maresins by 12/15-LOXs. (B) SPMs trigger their pro-resolving signals via designated GPCRs expressed on various cells, mainly immune cells. (C) Physiologically, acute inflammation terminates by SPM-mediated resolution, which involves restriction of neutrophil tissue infiltration, counter-regulation of pro-inflammatory chemokines and cytokines, reduction of ROS and NLRP3 inflammasome generation, induction of apoptosis in active neutrophils and their subsequent efferocytosis by macrophages, accumulation of anti-inflammatory M2 macrophages, and other related processes. Ultimately, the resolution process leads to tissue healing and restoration of tissue homeostasis. Down arrow means “decrease”, up arrow means “increase”. Further explanations are given in the text. Abbreviations: GPCR, G protein-coupled receptor; EPA, eicosapentaenoic acid; HEPE, hydroxyeicosapentaenoic acid; HpDHA, hydroperoxydocosahexaenoic acid; HpEPE, hydroperoxyeicosapentaenoic acid; MAPK, mitogen-activated protein kinase; JAK-STAT, Janus kinase (JAK)-signal transducer and activator of transcription (STAT); LOX, lipoxygenase; Lymph, lymphocyte; Mph, macrophage; Neu, neutrophil; NK, natural killer cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PUFA, polyunsaturated fatty acids; ROS, reactive oxygen species; SPMs, specialized pro-resolving molecules.
Figure 4
Figure 4
Proposed therapeutic strategy to attenuate the manifestations of RA and CC and reduce CC risk in patients with RA by reversing chronic inflammation and correcting dysbiosis. We assume that failure to resolve chronic inflammation, as well as gut and vaginal dysbiosis, are key factors in the pathogenesis of RA and CC, aggravated manifestations, and increased risk of CC development in RA patients. These processes appear to mutually interact, creating a vicious cycle that maintains and worsens both RA and CC. Accordingly, the use of stable SPM receptor mimetics and agonists, such as BML-111, the anti-ChemR23 agonist antibody (resolvin E1 receptor), and dysbiosis correction have promising therapeutic potential for these conditions. Those treatments are intended to complement traditional treatments for RA and CC. Further explanations are given in the text. Abbreviations: HPV, human papillomavirus; SPMs, specialized pro-resolving molecules; RA, rheumatoid arthritis.
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