Interleukin-17A (IL-17A) is a pro-inflammatory cytokine with well-characterized biological effects on stromal cell activation, angiogenesis, and osteoclastogenesis. The presence of this cytokine in ...the inflamed joints of patients with rheumatoid arthritis (RA), together with compelling data from in vitro and experimental arthritis models demonstrating its pro-inflammatory effects, made this cytokine a strong candidate for therapeutic targeting. Clinical trials, however, have shown relatively modest success in RA as compared with other indications. Guided by recent insights in IL-17 biology, this review aims to explore possible reasons for the limited clinical efficacy of IL-17A blockade in RA, and what we can learn from these results going forward.
Highlights • IL-17A (IL-17) is produced by multiple cell subsets, including CD8+ T cells. • The presence of IL-17+ CD8+ T cells in human inflammatory diseases suggests these cells may contribute to ...immunopathology. • Increased knowledge of human IL-17+ CD8+ T cells will enhance our overall understanding of their role in human disease.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial lining (synovitis). The inflammation in the RA joint is associated with and driven by immune ...cell infiltration, synovial hyperproliferation, and excessive production of proinflammatory mediators, such as tumor necrosis factor α (TNFα), interferon γ (IFNγ), interleukin (IL)-1β, IL-6, and IL-17, eventually resulting in damage to the cartilage and underlying bone. The RA joint harbors a wide range of immune cell types, including monocytes, macrophages, and CD4(+) T cells (both proinflammatory and regulatory). The interplay between CD14(+) myeloid cells and CD4(+) T cells can significantly influence CD4(+) T cell function, and conversely, effector vs. regulatory CD4(+) T cell subsets can exert profound effects on monocyte/macrophage function. In this review, we will discuss how the interplay between CD4(+) T cells and monocytes/macrophages may contribute to the immunopathology of RA.
Inflammation and immune resolution Taams, Leonie S.
Clinical and experimental immunology,
July 2018, Letnik:
193, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Summary
Inspired by the advances presented at the Inflammation and Immune Resolution Plenary Session at the British Society for Immunology Congress, December 2017, in this issue of Clinical & ...Experimental Immunology we present a Review Series on Inflammation and Immune Resolution. Our selection ranges from an overview of current genetic understanding of the similarities and differences between immune‐mediated inflammatory diseases (IMIDs); discussion of several biological mechanisms underlying the aberrant activation of myeloid cells in RA, and how myeloid cell relevant anti‐inflammatory mediators may contribute to immune resolution; presentation of fascinating evidence for the existence of innate immune memory in stromal cells and how this may exacerbate or restrain inflammatory disease; and a review of how the interleukin (IL)‐6 family members IL‐6 and IL‐27 may drive or regulate inflammation. Inflammation and immune resolution are two sides of the same coin: the reviews presented in this series aim to equip readers with greater insight into the delicate balance between the two.
Periodontitis (PD) is a chronic inflammatory disease characterised by tissue inflammation and destruction of the associated alveolar bone. It is caused by the colonisation of the bacterial plaque ...biofilm and the resultant host immune responses in the surrounding periodontal tissues. The pro‐inflammatory cytokine IL‐17, and IL‐17 producing CD4+ T cells (also called Th17 cells) have been shown to play an important role in many inflammatory diseases. There is increasing evidence of the presence of IL‐17 and Th17 cells in human PD lesions and this may be associated with disease severity. Moreover, several animal studies indicate the potential role of IL‐17 and Th17 cells in gingival inflammation and the resultant bone destruction in PD. Here we review recent findings regarding the presence, function and regulation of IL‐17 and Th17 cells in PD, and we highlight potential areas of future research interest.
CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) are potent suppressors of the adaptive immune system, but their effects on innate immune cells are less well known. Here we demonstrate a previously ...uncharacterized function of Tregs, namely their ability to steer monocyte differentiation toward alternatively activated macrophages (AAM). AAM are cells with strong antiinflammatory potential involved in immune regulation, tissue remodeling, parasite killing, and tumor promotion. We show that, after coculture with Tregs, monocytes/macrophages display typical features of AAM, including up-regulated expression of CD206 (macrophage mannose receptor) and CD163 (hemoglobin scavenger receptor), an increased production of CCL18, and an enhanced phagocytic capacity. In addition, the monocytes/macrophages have reduced expression of HLA-DR and a strongly reduced capacity to respond to LPS in terms of proinflammatory mediator production (IL-1β, IL-6, IL-8, MIP-1α, TNF-α), NFκB activation, and tyrosine phosphorylation. Mechanistic studies reveal that CD4⁺CD25⁺CD127lowFoxp3⁺ Tregs produce IL-10, IL-4, and IL-13 and that these cytokines are the critical factors involved in the suppression of the proinflammatory cytokine response. In contrast, the Treg-mediated induction of CD206 is entirely cytokine-independent, whereas the up-regulation of CD163, CCL18, and phagocytosis are (partly) dependent on IL-10 but not on IL-4/IL-13. Together these data demonstrate a previously unrecognized function of CD4⁺CD25⁺Foxp3⁺ Tregs, namely their ability to induce alternative activation of monocytes/macrophages. Moreover, the data suggest that the Treg-mediated induction of AAM partly involves a novel, cytokine-independent pathway.
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