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B cell-derived transforming growth factor-?1 expression limits the induction phase of autoimmune neuroinflammation.

ABSTRACT: Studies in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), have shown that regulatory B cells modulate the course of the disease via the production of suppressive cytokines. While data indicate a role for transforming growth factor (TGF)-?1 expression in regulatory B cell functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Transgenic mice deficient for TGF-?1 expression in B cells (B-TGF-?1^-/-) were tested in EAE induced by recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG). In this model, B-TGF-?1^-/- mice showed an earlier onset of neurologic impairment compared to their littermate controls. Exacerbated EAE susceptibility in B-TGF-?1^-/- mice was associated with augmented CNS T helper (Th)1/17 responses. Moreover, selective B cell TGF-?1-deficiency increased the frequencies and activation of myeloid dendritic cells, potent professional antigen-presenting cells (APCs), suggesting that B cell-derived TGF-?1 can constrain Th1/17 responses through inhibition of APC activity. Collectively our data suggest that B cells can down-regulate the function of APCs, and in turn encephalitogenic Th1/17 responses, via TGF-?1, findings that may be relevant to B cell-targeted therapies.

SUBMITTER: Bjarnadottir K

PROVIDER: S-EPMC5052622 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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B cell-derived transforming growth factor-β1 expression limits the induction phase of autoimmune neuroinflammation.

Bjarnadóttir Kristbjörg K Benkhoucha Mahdia M Merkler Doron D Weber Martin S MS Payne Natalie L NL Bernard Claude C A CCA Molnarfi Nicolas N Lalive Patrice H PH

Scientific reports 20161006

Studies in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), have shown that regulatory B cells modulate the course of the disease via the production of suppressive cytokines. While data indicate a role for transforming growth factor (TGF)-β1 expression in regulatory B cell functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Transgenic mice deficient for TGF-β1 expression in B cells (B-TGF-β1<sup>-/-</sup>) were tested in E ...[more]

PMID: 27708418

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Project description:Transforming growth factor-?s (TGF-?s) regulate cellular proliferation, differentiation, and survival. TGF-?s bind to type I (TGF-?RI) and II receptors (TGF-?RII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-?RIII). TGF-? may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-? is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-?1-3 after MCAO. To establish how TGF-?s exert their actions following MCAO, the present study describes the induction of TGF-?RI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-?RI had significant expression: neurons in cortical layer IV contained TGF-?RI. At 24 h after the occlusion, no TGF-? receptors showed induction. At 72 h following MCAO, all four types of TGF-? receptors were induced in the infarct area, while TGF-?RI and RII also appeared in the penumbra. Most cells with elevated TGF-?RI mRNA levels were microglia. TGF-?RII co-localized with both microglial and endothelial markers while TGF-?RIII and Alk1 were present predominantly in endothels. All four TGF-? receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-?RIII was further induced as compared to 72 h after MCAO. At this time point, TGF-?RIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-? receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-? receptor expression is preceded by increased TGF-? expression. TGF-?RI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-?RII, and RIII in endothels within the infarct where TGF-?1 may be their ligand. At later time points, TGF-?RIII may also appear in glial cells to potentially affect signal transduction via TGF-?RI and RII.

Project description:IntroductionThe objective of this study was to model the effects of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF), both present in rheumatoid arthritis (RA) synovia, on the behavior of fibroblast-like synoviocytes (FLS) in response to pro-inflammatory cytokine (interleukin (IL)1beta, tumor necrosis factor-alpha (TNFalpha)) challenge.MethodsGene and protein expression by fibroblast-like synoviocytes in vitro was studied by quantitative Polymerase Chain Reaction (qPCR), ELISA and multiplex bead cytokine assays. Intracellular signaling pathway activation was determined by Western blot for phospho-kinases and the use of specific inhibitors.ResultsIn combination, TGF-beta and PDGF (2GF) synergistically augmented TNFalpha- or IL1beta-induced matrix metalloproteinase 3 (MMP3), IL6, IL8, and macrophage inflammatory protein 1 alpha (MIP1alpha) secretion by FLS. Other FLS-derived mediators remained unaffected. Individually, neither growth factor significantly potentiated TNFalpha or IL1beta-induced MMP3 secretion, and only slightly enhanced IL6. The effect of 2GF on TNFalpha-induced gene expression was transcriptionally mediated; blocked by imatinib mesylate; and occurred even if 2GF was added as much as four hours prior to TNFalpha. In addition, a 15-minute pulse of 2GF four hours prior to TNFalpha stimulation yielded a synergistic response. The extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling pathways were induced for at least four hours by 2GF, as demonstrated by persistently upregulated levels of phospho-Akt and phospho-ERK. However, pharmacologic inhibitor studies demonstrated that the potentiating action of 2GF was dependent on PI3 kinase only, and not on ERK.ConclusionsThe combination of PDGF and TGF-beta dramatically potentiates FLS response to cytokines in a receptor-mediated and PI3 kinase-dependent fashion. These data suggest that 2GF contribute to synovitis by directing synovial fibroblasts toward a more aggressive phenotype in response to TNFalpha. Therefore, inhibition of growth factor signaling may constitute a complementary therapeutic approach to cytokine-targeted treatments for RA.

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B cell-derived transforming growth factor-?1 expression limits the induction phase of autoimmune neuroinflammation.

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B cell-derived transforming growth factor-β1 expression limits the induction phase of autoimmune neuroinflammation.

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