Activation of dendritic cells – adiponectin
A study published in March 2013 issue of the Journal of Immunology identifies a new immunomodulatory effect of adiponectin (APN) – its ability to activate DCs through PLCγ/JNK/NF-κB-signaling pathways and release of proinflammatory cytokines, and to potentiate Th1 and Th17 immune responses.
Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels as well as fatty acid breakdown. Adiponectin is secreted from adipose tissue (and also from the placenta in pregnancy) into the bloodstream and is very abundant in plasma relative to many hormones. In the bloodstream it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL (mg/L).
Adiponectin is the most abundant peptide secreted by adipocytes, whose reduction plays a central role in obesity-related diseases, including insulin resistance/type 2 diabetes and cardiovascular disease. Other cell types, such as skeletal and cardiac myocytes and endothelial cells, can also produce this adipocytokine.
Adiponectin (APN) exists as multimeric forms in plasma: trimer, hexamer, high m.w. oligomer (HMW), and a free globular domain.
The pro- versus anti-inflammatory effects of APN are complex and not well understood. Thus, previous reports indicated that APN suppresses inflammatory responses induced by TNF-α, whereas others reported that APN by itself activates NF-κB and promotes inflammatory cytokine production. APN is an important regulator of cytokine responses, and this effect is isoform specific. HWM APN increases IL-6 secretion in human monocytes and human monocytic leukemia cell line cells, but low m.w. APN reduces LPS-mediated IL-6 release and also stimulates IL-10 secretion.
Adiponectin is known for its insulin-sensitizing effects, is an indicator of the onset of some cardiovascular diseases, such as coronary artery disease and essential hypertension. Increased concentrations of APN are reported in chronic inflammatory diseases, such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis. It appears that APN expression is closely associated with the pathology of chronic inflammatory and autoimmune diseases.
In the Journal of Immunology study, Mi Jung and colleagues from the School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea, demonstrate that APN is able to activate dendritic cells through enhancement of the co-stimulatory molecules and MHC class II, and release of proinflammatory cytokines, thus leading to Th1 and Th17 polarization and phenotypes.
Pretreatment with a phospholipase C (PLC)γ inhibitor and a JNK inhibitor suppressed IL-12 production and NF-κB binding activity. APN-treated DCs significantly induced both Th1 and Th17 responses in allogeneic CD4+ T cells. The addition of a neutralizing anti–IL-12 mAb to the cocultures abolished the secretion of IFN-γ, whereas the blockage of IL-23 and IL-1β suppressed APN-induced IL-17 production.
Using RT-PCR analysis, the authors found that primary immature DCs (iDCs) express both AdipoR1 and AdipoR2 receptor isoforms. In addition, APN slightly increased the expression of AdipoR1 but not AdipoR2.
Although previous research indicates that APN is an anti-inflammatory protein, upregulation of IL-12 and IL-6 by APN reflects the proinflammatory effects of this adipokine. APN is known to exert significant proinflammatory and matrix-degrading effects.
The results of this study suggest that IL-23, IL-1, and IL-6 are capable of inducing the development of Th17 cells. Blockage of IL-23p19 alone significantly suppressed IL-17 production.
The authors discuss that APN is able to induce the production of IL-6, matrix metalloproteinase-1, and IL-8 from RA synovial fibroblasts in vitro, and that an inflammation loop linking IL-1–IL-23–IL-17 axis and further enhancement of IL-23 and IL-1 production through T cell feedback may amplify the APN-mediated differentiation of Th17 cells. Thus, the authors speculate that APN-mediated Th17 responses can be induced by a variety of cytokine combinations, including IL-1β, IL-6, and IL-23.
Through these mechanisms, APN may contribute to Th1- and Th17-mediated inflammatory and/or autoimmune diseases. Thus, increased levels of APN released locally at the inflammatory site, such as in established colitis and arthritis, may contribute to the perpetuation of inflammation, exacerbating the disease process.
Source: J Immunol, 2012 Mar 15; 188:2592. doi: 10.4049/jimmunol.1102588. Epub 2012 Feb 15.
Updates
A 2015 study investigated the role of adiponectin in regulating Th17 response and the expression of receptor activator of nuclear factor-κB ligand (RANKL) in mice with collagen-induced arthritis (CIA).
Adiponectin injection resulted in an earlier onset of arthritis, an aggravated arthritic progression, more severe synovial hyperplasia, bone erosion and osteoporosis in CIA mice. CD4+IL-17+ Th17 cells, IL-17 mRNA and RANKL mRNA expression were markedly increased in the joint tissue of adiponectin treated CIA mice.
Moreover, adiponectin treatment markedly enhanced Th17 cell generation from naive CD4+ T cells in vitro, which accompanied by the high expression of Th17 transcription factor ROR-γt, and Th17 cytokine genes included IL-22 and IL-23. This study reveals a novel effect of adiponectin in exacerbating CIA progression by enhancing Th17 cell response and RANKL expression.
The authors of this study concluded that adiponectin can promote the differentiation of naïve T cell to Th17 cell and upregulate RANKL/OPG ratio, resulting in an enhanced synovitis and bone erosion in CIA models. These findings reveal a novel role of AD in mediating the development of autoimmune arthritis in mice.
A 2024 study demonstrated that Adipor1 knockout significantly reduced the proportion of naïve CD4+ T cells differentiating into pTh17 cells. We also found that the loss of Adipor1 in pTh17 cells resulted in gene expression profiles similar to those observed in WT npTh17 cells.
Background: Th17 cells may differentiate into pathogenic (pTh17) and non-pathogenic (npTh17) cells, with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions.
Adiponectin exerts its biological function through its receptors, AdipoR1 and AdipoR2. AdipoR1 is highly expressed in skeletal muscle, whereas AdipoR2 is highly expressed in the liver and kidneys.
The results indicate that AdipoR1 is essential for the development and activity of pTh17 cells, and its absence skews these cells towards an npTh17-like phenotype.
The authors of this study concluded that this research is the first to demonstrate that Adipor1 knockout upregulates FUNDC1 expression, thereby inhibiting pTh17 differentiation through mitochondrial dysfunction.
This establishes a novel molecular mechanism by which AdipoR1 regulates the pTh17 pathway to affect rheumatoid arthritis as well as other autoimmune and inflammatory diseases mediated by pTh17. This highlights the potential of targeting AdipoR1 to modulate pTh17 cell activity in treatment strategies for rheumatoid arthritis.
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