Pro-Inflammatory Th17 – Glucocorticoid-Resistant
A recent study by Radha Ramesh and colleagues, published in the Journal of Experimental Medicine indicates that the expression of the multi-drug transporter MDR1 (also known as P-glycoprotein [P-gp] and ABCB1) is a marker that defines the pro-inflammatory nature of T helper (Th)17 cells.
It appears that Th17 cells are key drivers of inflammation in multiple autoimmune diseases. The Th17 cells are major players in inflammatory/autoimmune conditions, but not all Th17 cells are inflammatory. In mice, a subset of nonpathogenic Th17 cells develop in the absence of interleukin (IL)-23/IL-23R; produce IL-17A along with IL-10; and may exert anti-inflammatory effects.
Conversely, data in humans indicate that in response to IL-23, memory lymphocytes expand into a Th17 phenotype, with a subpopulation of cells simultaneously expressing IFN-γ and IL-17. Importantly, it appears that the co-expression of IL-17A and IFN-γ is a hallmark of T cells isolated from inflamed tissues. In addition, the cellular responses to IL-23 and the IL-23R expression levels may distinguish between pro- and anti-inflammatory Th17 cells.
Of note, the study of Rameshet al. demonstrates that IL-23R expression does not mark the ‘canonical’ Th17; it is increased, however, in CCR6+ Th17 subsets that display Th1-like properties (i.e., Th17.1 cells expressing IFN-γ and CXCR3). Importantly, the authors of this study show that both high-level IL-23R expression and marked functional responses to IL-23 stimulation are confined to a subset of Th17.1 cells that expresses the multi-drug transporter MDR1/P-gp.
Furthermore, the study also uncovered that MDR1+ Th17.1 cells are highly sensitive to IL-23 stimulation, are increased within the gut tissue of Crohn’s disease patients, and are resistant to the anti-inflammatory actions of several glucocorticoids.
According to the authors, these features reveal the pathogenic nature of these cells. They may be relevant to several inflammatory and autoimmune conditions, and the development of new therapeutic approaches for immune-mediated diseases.
Source: J Exp Med 2014, 211:89-104. doi: 10.1084/jem.20130301. Epub 2014 Jan 6.
Read More: Journal of Experimental Medicine
In a 2015 study published in the Arthritis & Rheumatology, David Saadoun and colleagues from the Pierre and Marie Curie University, Paris, France demonstrated that the Th17 and Th1 pathways contribute to the systemic and vascular manifestations of in Takayasu arteritis (TA).
This is perhaps the first report to demonstrate that T helper (Th)1 and Th17 cells and cytokine pathways may play central role in driving systemic inflammation in this condition. Importantly, the study also showed that TA patients under GCs therapy had decreased circulating Th1-related cytokines such as TNF-α, IL-2 and IFN-γ. However, the inhibitory effect of GCs spared Th17-related cytokines, corroborating previous studies that point out the glucocorticoid resistance of Th17 cells.
In a 2016 study published in Immunology Ana Cristina Wing and colleagues showed that L-17- and IL-22-secreting CD4+ T cells resistant to corticoids are associated with radiological activity of the MS in early stages of the disease, mainly among Afrodescendant patients who, normally, have worse prognosis.
Multiple sclerosis (MS) is an autoimmune disease, where myelin-reactive T cells damage the myelin sheet in the central nervous system. Human Th17 cells migrate more efficiently than Th1 cells, and display cytotoxic activity against neurons; and there is an enrichment of T cells expressing both IL-17 and IFN-γ in MS brain tissue.
In the Immunology report, Ana Cristina Wing and colleagues from the Federal University of the State of Rio de Janeiro, Brazil, studied 22 patients with relapsing-remitting MS, at the early stage of the disease (range 2-23 months). The authors of this study found a direct relationship between the production of in vitro IL-17 and IL-22 by MBP-specific CD4+ T cells and the number of active brain lesions in MS patients at the early stage of disease. Importantly, in those patients, the corticoid was less efficient in modulating the release of both cytokines.
Thus, the inhibitory effect of glucocorticoids, on the production of IL-17 and IL-22 was inversely related to the number of active brain lesions; with the important observation that Afro-descendants, when compared to Caucasians, expressed higher production of both IL-17 and IL-22 production that was related to a pronounced glucocorticoid resistance of their T cells.
In a 2017 review in Allergy by J. Banuelos and colleagues from the Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL compared the glucocorticoid sensitive and resistant immunological diseases and suggested that several aspects in Th-17 related diseases alter glucocorticoid sensitivity of Th17 cells.
These authors focused their attention on the different glucocorticoid (GC) sensitivity/resistance of Th17 cells observed in different inflammatory diseases. For example, Th17 are sensitive to GC treatment in psoriasis while they are resistant in Crohn’s disease. The authors suggest that differences in molecular patterns characterizing human chronic inflammatory diseases strongly influence GC sensitivity of Th17.
The authors of this review concluded that different subsets of Th17 cells with distinct GC sensitivity probably exist, and long-term GC treatment could deplete GC-sensitive T cells and promote the expansion of GC resistant subsets, thus sustaining the inflammatory process. As per these authors it will be interesting to determine whether in the same individual, long-term glucocorticoid treatment shifts the etiology of a disease from glucocorticoid-sensitive to a resistant Th subset. Another intriguing question is whether rheumatoid arthritis and Crohn’s disease, like asthma, can be categorized into endotypes with distinct underlying T helper cell subsets and glucocorticoid sensitivity.
For an overview and more information about these effects and the glucocorticoid sensitivity and resistance of Th17 cells, see the evolving concept article Pro-inflammatory Th17 cells and glucocorticoid resistance.