Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis

Abstract

CD44 is a transmembrane molecule appearing in numerous isoforms generated by insertions of alternatively spliced variant exons (CD44v) and having various binding partners. CD44v7 on T cells was proposed to promote colitis by preventing T-cell apoptosis. Here we demonstrate that Cd44v7-deficient T cells - like Cd44 wild-type (Cd44) T cells - provoked disease in two different colitis models: the model induced by CD4CD45RB T-cell transfer into Rag2-deficient mice and a new model based on ovalbumin (OVA)-specific T-cell transfer into Rag-sufficient, OVA-challenged mice. In contrast, CD44v7 absence on macrophages in recipient mice prevented colitis. Prevention was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3)-activating and Foxp3-counteracting interleukin-6 (IL-6), lower numbers of phospho-STAT3-containing lymphocytes, and higher Foxp3 T-cell counts in the colon. Consequently, the protected colons showed lower IL-12, IL-1β expression, and decreased interferon-γ levels. Importantly, stimulation of T cells by Cd44v7-deficient macrophages induced upregulation of Foxp3 in vitro, while cotransfer of Cd44 macrophages into Cd44v7-deficient mice reduced Foxp3 T-cell counts and caused colitis. Accordingly, the CD44v7 ligand osteopontin, whose levels were elevated in Crohn's disease, specifically induced IL-6 in human monocytes, a cytokine also increased in these patients. We suggest macrophage-specific targeting of the CD44v7 pathway as a novel therapeutic option for Crohn's disease.

Urinary Proteomics Profiles Are Useful for Detection of Cancer Biomarkers and Changes Induced by Therapeutic Procedures

“…Moreover, high levels of OPN have been found in cerebrospinal fluid and serum of cancer patients [46] and it is considered a possible target for cancer therapy [23]. It is to be noted that the role in inflammation of OPN is possibly mediated by CD44 isoforms [47,48], suggesting that a specific inflammatory pathway could be the target of BSH or BPA.…”

Exploration of key ferroptosis-related genes and immune infiltration in Crohn’s disease using bioinformatics

“…Liu et al revealed that CD44 expression inhibited ferroptosis in cancer cells in an OTUB1-dependent manner 34 . It has been suggested that the absence of specific CD44 variable splice exons in macrophages prevents CD 35 . It remains to be investigated whether CD44 , a ferroptosis inhibitor, could exacerbate CD by reducing ferroptosis in CD.…”

“…Earlier studies have shown that soluble caveolin-1-Ig inhibits T cell proliferation and cytokine production in response to recall antigen or alloantigen-presenting cells (APC), and in combination with our study, CAV1 was negatively correlated with memory resting CD4 + T cells, suggesting that CAV1 may be involved in CD progression by inhibiting T cell proliferation 52 . CD44 has been shown to block apoptosis of CD4 + T cells that activate colitis 35 , 53 . The inhibitor of ferroptosis, CD44 , was negatively correlated with memory resting CD4 + T cells in the present study, which may suggest that CD44 exacerbates CD in the intestine by inhibiting apoptosis or ferroptosis of CD4 + T cells.…”

Crosstalk between alternative splicing and inflammatory bowel disease: Basic mechanisms, biotechnological progresses and future perspectives

“…CD44v7 deletion in macrophages of recipient mice might link to the down‐regulation of STAT3‐activating and forkhead box P3 (Foxp3)‐counteracting IL‐6, which would cause decreased numbers of phospho‐STAT3‐containing lymphocytes as well as elevated counts of Foxp3 + T‐cells in the gut (Figure 5A). 86 TL1A as well as its functional receptor (death‐domain receptor 3, DR3) have been considered as the key members of TNF/tumour necrosis factor receptor superfamilies of proteins. Once APC‐derived TL1A is bound to the lymphocytic DR3, TL1A–DR3 interaction exerts pleiotropic effects on different adaptive immune cells, including Treg and helper T cells, to influence cell proliferation, maintenance and differentiation 87,88 .…”