Osteopontin expression by CD103⁻dendritic cells drives intestinal inflammation

Abstract

Intestinal CD103 − dendritic cells (DCs) are pathogenic for colitis. Unveiling molecular mechanisms that render these cells proinflammatory is important for the design of specific immunotherapies. In this report, we demonstrated that mesenteric lymph node CD103 − DCs express, among other proinflammatory cytokines, high levels of osteopontin (Opn) during experimental colitis. Opn expression by CD103 − DCs was crucial for their immune profile and pathogenicity, including induction of T helper (Th) 1 and Th17 cell responses. Adoptive transfer of Opn-deficient CD103 − DCs resulted in attenuated colitis in comparison to transfer of WT CD103 − DCs, whereas transgenic CD103 − DCs that overexpress Opn were highly pathogenic in vivo. Neutralization of secreted Opn expressed exclusively by CD103 − DCs restrained disease severity. Also, Opn deficiency resulted in milder disease, whereas systemic neutralization of secreted Opn was therapeutic. We determined a specific domain of the Opn protein responsible for its CD103 − DC-mediated proinflammatory effect. We demonstrated that disrupting the interaction of this Opn domain with integrin α9, overexpressed on colitic CD103 − DCs, suppressed the inflammatory potential of these cells in vitro and in vivo. These results add unique insight into the biology of CD103 − DCs and their function during inflammatory bowel disease.

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease

“…RNA extraction, quantification, and cDNA synthesis from isolated DCs or CD4 + T cells were performed as previously described (20). Primers were designed using the Primer 3 program and are as follows: Tigit sense primer, 59-GTGGGATTTACAAGGGGAGA-39 and antisense, 59-CTTCCAGGG-GATGAGAGAC-39; Gata3 sense primer, 59-TTACCACCTATCCGCCC-TAT-39 and antisense, 59-ACACACTCCCTGCCTTCTG-39; Cd226 sense primer, 59-CAAGAACACTGGCACAAAGA-39 and antisense, 59-GAAA-CAAGCAGGAGTAGATGC-39; c-maf sense primer, 59-CCCTTGA-CAGTTTGCTTCTA-39 and antisense, 59-CCCATTCTGCTATCTTTGAC-39; Rorc sense primer, 59-TGTTTTATGGGGTTTGGGTA-39 and antisense, 59-AAGAGATTGTGTGCCAGAG-39; and Tbx21 sense primer, 59-TAGTGATTGGTTGGAGAGGA-39 and antisense, 59-GTAGTTCGGGCA-GAGAAAG-39 (Eurofins MWG).…”

“…Primers for Cd155 were previously described (15). Real-time PCR was performed as previously described (20).…”

ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity

“…RNA extraction, quantification, and cDNA synthesis were performed as previously described (17). The sequences of RT-PCR primers used for mRNA relative expression analysis in this study were designed using the Tgfb1 FW: 59-CCTGGGTTGGAAGTGGA-39, Tgfb1 Rev: 59-TAGTA-GACGATGGGCAGT-39.…”

“…The sequences of RT-PCR primers used for mRNA relative expression analysis in this study were designed using the Tgfb1 FW: 59-CCTGGGTTGGAAGTGGA-39, Tgfb1 Rev: 59-TAGTA-GACGATGGGCAGT-39. Real-time PCR was performed as previously described (17).…”

Multiple sclerosis and susceptibility to celiac disease: An osteopontin gene haplotypes affair?

“…In addition, it has been observed that Th17 cytokine IL-17 levels enhance in CD [9]. OPN has been found to be over-expressed in plasma and intestinal tissue from patients with inflammatory bowel diseases and CD [12,13]. OPN expression by intestinal CD103-dendritic cells (DCs) has been demonstrated to drive intestinal inflammation [12,13].…”