Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

Abstract

Th17 cells are critical effectors in inflammation and tissue damage such as bone erosion, but the mechanisms regulating their activation in this process are not fully understood. In this study, we considered the cooperation between cytokine receptors and integrin pathways in Th17-osteoclast function. We found that human Th17 cells coexpress IL-7R and the collagen-binding integrin α2β1 (CD49b), and IL-7 increases their adhesion to collagen via α2β1 integrin. In addition, coengagement of the two receptors in human Th17 cells cooperatively enhanced their IL-17 production and their osteoclastogenic function. The functional cooperation between IL-7R and α2β1 integrin involves activation of the JAK/PI3K/AKT (protein kinase B) and MAPK/ERK pathways. We also showed that IL-7–induced bone loss in vivo is associated with Th17 cell expansion. Moreover, blockade of α2β1 integrin with a neutralizing mAb inhibited IL-7–induced bone loss and osteoclast numbers by reducing Th17 cell numbers in the bone marrow and reducing the production of IL-17 and the receptor activator of NF-κB ligand. Thus, the cooperation between IL-7R and α2β1 integrin can represent an important pathogenic pathway in Th17-osteoclast function associated with inflammatory diseases.

Cytokine response to Hantaan virus infection in patients with hemorrhagic fever with renal syndrome

“…IL‐7 is not an inflammatory cytokine and plays important role in T/B cell maturation. It has also been shown that IL‐7 can promote Th17 cell proliferation . We found an apparent increase in IL‐17 in severe HFRS patients, but the correlation requires further data.…”

The integrin–collagen connection – a glue for tissue repair?

“…The absence of α2 is known to delay fibrosis and glomerular damage in experimental kidney disease models, including the Alport syndrome mouse model (Borza et al, 2012;Rubel et al, 2014). Moreover, another more recent study has demonstrated a role for α2β1 in inflammation during rheumatoid arthritis, with reduced disease severity in integrin α2 −/− mice (El Azreq et al, 2015). Somewhat surprisingly, this protective effect was not due to the absence of α2 on immune cells as reported in a previous study (Gillberg et al, 2013).…”

“…Reduced experimental arthritis (Peters et al, 2012), reduced DSS colitis (Gillberg et al, 2013;Lundberg et al, 2006), reduced bone loss (El Azreq et al, 2015), reduced inflammatory response of mast cells (Edelson et al, 2004), increased vascularization and reduced insulin resistance in diabetes model (Kang et al, 2011).…”

“…Studies of aging bone and cartilage further revealed defects in bone collagen dynamics and delayed age-induced osteoporosis in α2-deficient mice (Peters et al, 2012;Stange et al, 2013). Three decades after identification of the cell surface protein VLA-2 on T-cells (Hemler et al, 1985b), a recent study demonstrated that α2β1 cooperates with the interleukin 7 (IL-7) receptor on Th17 cells to mediate bone loss (El Azreq et al, 2015). Polymorphisms in the coding region of the α2 gene ITGA2 have been observed to regulate α2 levels on human platelets (Kuncki and Nugent, 2010); and alleles encoding these variants were found in a separate study to be associated with an increased risk of thrombosis and myocardial (A) Integrin α11β1 in collagen reorganization.…”

Discoidin domain receptor 1 promotes Th17 cell migration by activating the RhoA/ROCK/MAPK/ERK signaling pathway

“…DDR1 protein and ERK phosphorylation levels were determined by western blot analysis using anti-DDR1 (C20) and anti-phosphorylated ERK1/2 (clone E-4) antibodies as we previously described [54]. The blots were stripped and reprobed with control antibodies.…”