Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis

Abstract

BackgroundInterleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer.MethodsWe examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a−/− mice and in T- and B-cell-deficient Rag2−/− mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression.ResultsTreatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a−/− mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a−/− mice treated with an anti-IL-7R antibody. In Rag2−/− mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity.ConclusionsResults from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.

IL7RA haplotype-associated alterations in cellular immune function and gene expression patterns in multiple sclerosis

“…The IL-7/IL-7R system has been described to play a role in MS as well as in other autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and inflammatory bowel disease 24,33,34 . There is compelling evidence from animal models of these diseases that blocking of the IL-7RA leads to an amelioration of the disease course by modulating inflammatory processes [22][23][24]33,34 .…”

“…There is compelling evidence from animal models of these diseases that blocking of the IL-7RA leads to an amelioration of the disease course by modulating inflammatory processes [22][23][24]33,34 . .…”

Anti‐IL‐7 receptor α monoclonal antibody (GSK2618960) in healthy subjects – a randomized, double‐blind, placebo‐controlled study

“…An increasing body of both preclinical and clinical evidence suggests that raised expression levels of interleukin (IL)-7 and/or the IL-7 receptor (IL-7R) are associated with various disease states, including rheumatoid arthritis [1][2][3], juvenile idiopathic arthritis [4], spondyloarthritis [5], psoriasis [6], primary Sjögren's syndrome [7][8][9][10], colitis [11], type 1 diabetes [12,13] and multiple sclerosis [14,15]. Genome-wide association studies have also identified genetic variations in IL-7R as a risk factor for some autoimmune diseases [16,17].…”

Smoking affects gene expression in blood of patients with ischemic stroke

“…IL7 regulates T‐cell differentiation, survival, and homeostasis, which mediates inflammation upon binding to IL7R . Increased gene expression of IL7R and lnc‐IL7R are observed in many inflammatory conditions including atherosclerotic plaques in humans . Thus, the dysregulation of some of the above T‐cell receptor signaling pathways could contribute to worsened ischemic brain injury in smokers.…”