Psoriatic arthritis (PsA) is a persistent, inflammatory disease that affects individuals with psoriasis, arthritis, and enthesitis. Research has demonstrated that inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-23 (IL-23), and interleukin-17 (IL-17) play a pivotal role in both the onset and progression of PsA. These cytokines are generated by activated immune cells and stimulate the attraction of inflammatory cells to the synovium and joint tissues, resulting in the deterioration of cartilage and bone. The blocking of these cytokines has become a successful treatment strategy for PsA, as biological drugs that inhibit TNF-α, IL-23, and IL-17 have demonstrated notable clinical benefits. The association between PsA and other types of inflammatory cytokines or chemokines, excluding TNF-α, IL-23, and IL-17, has been extensively investigated in numerous studies. These findings may provide a chance for the discovery of novel therapeutic agents targeting other molecules, distinct from the currently approved biologics and targeted synthetic disease-modifying anti-rheumatic drugs. In this review, we discuss the current understanding of the role of inflammatory cytokines in PsA pathogenesis and clinical implications of targeting these cytokines for PsA treatment.

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregulation of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK)1, which plays a role in necroptosis. We investigated whether NST-1s decreases inflammatory cell death and inflammatory responses in a mouse model of collagen-induced arthritis (CIA). NST-1s decreased the progression of CIA and the synovial expression of proinflammatory cytokines. Moreover, NST-1s treatment decreased the expression of necroptosis mediators such as RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL). In addition, NST-1s decreased osteoclastogenesis in vitro and in vivo. NST-1s downregulated T helper (Th)1 and Th17 cell expression, but promoted Th2 and regulatory T (Treg) cell expression in CIA mice. These results suggest that NST-1s attenuates CIA progression via the inhibition of osteoclastogenesis and might be a potential therapeutic agent for RA therapy.

Ha-Hee Son, M.D., Su-Jin Moon, M.D., Ph.D.. J Rheum Dis -0001;0:. https://doi.org/10.4078/jrd.2024.0129

Introduction: Mesenchymal stem cells (MSCs) can protect bone marrow transplantation (BMT) recipients from the lethal acute graft-versus-host disease (aGVHD) development. However, the mechanisms underlying the anti-inflammatory properties of MSCs in aGVHD remain to be elucidated. The immunoregulatory properties of MSCs are mediated by their production of anti-inflammatory molecules, including IL-10 and TGF-β. On the other hand, MSCs can also produce proinflammatory cytokines during their normal growth, such as IL-1β and IL-6. These opposite actions may limit their therapeutic application in aGVHD. Therefore, optimization of the functional properties of MSCs can increase their benefits.Methods: The expressions of mRNA and protein were analyzed by real-time PCR and western blotting, respectively. Expression of MSC markers was assessed by flow cytometry. An animal model of aGVHD was established by transplanting C57BL/6 donor bone marrow cells and spleen cells into lethally irradiated BALB/c recipient mice. The recipient mice were divided into the control group and the therapy [adipose tissue-derived human MSCs (Ad-hMSCs) or rapamycin-treated Ad-hMSCs] groups. The survival, body weight and clinical score of aGVHD in transplanted mice were monitored.Results: Rapamycin pre-treatment of Ad-hMSCs increased mRNA synthesis of IL-10, indoleamine 2,3-dioxygenase, and TGF-β compared with untreated Ad-hMSCs. Rapamycin-treated Ad-hMSCs suppressed clonal expansion of interleukin-17-producing CD4⁺T (Th17) cells more effectively than untreated cells. mRNA expression of autophagy markers such as ATG5, LC3A and LC3B was significantly increased in the rapamycin-treated Ad-hMSCs compared with untreated Ad-hMSCs. Transmission electron microscopy revealed that Ad-hMSCs exposure to rapamycin resulted in the appearance of autophagic vacuoles. Interestingly,in vitromigration efficiency of rapamycin-treated Ad-hMSCs toward the CD4⁺T cells was increased significantly compared with the untreated cells. And, these effects were associated with autophagy induction capacity of rapamycin.In vivo, the inhibiting properties of MSCs on the clinical severities of aGVHD were greater in the mice receiving rapamycin-treated Ad-hMSCs compared with untreated Ad-hMSCs. The beneficial effects of rapamycin treatment in Ad-hMSCs shownin vivowere associated with a reduction of Th17 cells and an increase in regulatory T cells.Conclusions: Rapamycin can optimize the immunomodulatory potential of Ad-hMSCs, suggesting a promising strategy of MSC use in aGVHD treatment.

Ko KM, et al. Yonsei Med J. 2020 May;61(5):406-415. https://doi.org/10.3349/ymj.2020.61.5.406