Osteopontin-dependent regulation of Th1 and Th17 cytokine responses in Trypanosoma cruzi-infected C57BL/6 mice

Santamaría, Miguel H.; Corral, Ricardo S.

doi:10.1016/j.cyto.2012.10.027

Cited by 22 publications

(15 citation statements)

References 43 publications

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“…In line with our observation that TLR2 signaling can be an important mediator of Th17 cell responses, Kim et al [70] reported that S. aureus can induce Th1 and Th17 inflammation, mainly in a TLR2-dependent manner, and TLR2 signaling has been shown to be an important molecular mediator of effective Th17 cell responses during Mycobacterium tuberculosis infections [71]. In addition, recent data show that OPN represents an important regulatory factor of the protective Th17 immunity in Trypanosoma cruzi infection [72], in which TLR2 has a predominant, immunoregulatory role [73].…”

Section: Discussionsupporting

confidence: 73%

Dual regulation of osteopontin production by TLR stimulation in dendritic cells

Salvi

Scutera²,

Rossi³

et al. 2013

Journal of Leukocyte Biology

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OPN, a cytokine produced, among others, by DCs, is involved in inflammation and defense against pathogens. Here, we report that the activation of the MyD88 pathway by TLR2, TLR5, and TLR7/8 agonists or IL-1β induces high levels of OPN in human DCs. Conversely, LPS and Poly I:C, two TLR3 and TLR4 agonists that engage the TRIF pathway, were ineffective. TLR2 agonists were the strongest OPN inducers, and OPN production was highly stimulated by TLR2-triggering bacteria (Staphylococcus aureus) but not by TLR4-triggering Escherichia coli. Costimulation experiments revealed that TLR3 and TLR4 agonists, beyond being inactive by themselves, sharply limited TLR2-dependent OPN production by activating a TRIF-dependent inhibition of the MyD88-dependent OPN production. MyD88 silencing impaired TLR2-dependent OPN induction, whereas TRIF pathway blockage by chloroquine, dynasore, or TRIF knockdown prevented the TLR3/4 agonist-mediated inhibition, which was independent from the endogenous production of type I IFN, IL-29, IL-10, or TGF-β. LPS and Poly I:C inhibitory activity was associated with the release of a >10-kDa protein factor(s). We also demonstrated that the higher OPN levels produced by S. aureus-treated DCs compared with E. coli-treated DCs were responsible for a markedly increased production of IL-17 by CD4⁺ T cells. These results highlight the biological relevance of the differential OPN induction by TLR2 and TLR4 agonists and emphasize the importance of TLR cross-talk in OPN induction. This implies that OPN regulation by TLR signaling is critical in shaping inflammatory responses and may modulate IL-17 production in response to pathogens.

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Section: Discussionsupporting

confidence: 73%

Dual regulation of osteopontin production by TLR stimulation in dendritic cells

Salvi

Scutera²,

Rossi³

et al. 2013

Journal of Leukocyte Biology

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“…Spp1 , which is also known as osteopontin, can play a role in the differentiation of T-helper 1 and T-helper 17 cells, which can cause tissue damage by producing proinflammatory cytokines (immunopathology). 50 These results suggested that acquired immune responses, particularly T-helper 1 and T-helper 17 responses, could be active in the hearts of infected mice, because MHC class II molecules on antigen-presenting cells contribute to the activation of MHC class II–restricted CD4 + T cells, which can promote immuno-globulin production from B cells. Thus, in this phase, both innate and acquired immune responses, particularly cellular immunity (T cells, NK cells, and NKT cells), rather than humoral immunity or viral replication, seemed to play effector roles.…”

Section: Discussionmentioning

confidence: 92%

Bioinformatics Multivariate Analysis Determined a Set of Phase-Specific Biomarker Candidates in a Novel Mouse Model for Viral Myocarditis

Omura

Kawai

Sato

et al. 2014

Circ Cardiovasc Genet

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Background Myocarditis is an inflammatory disease of the cardiac muscle and is mainly caused by viral infections. Viral myocarditis has been proposed to be divided into 3 phases: the acute viral phase, the subacute immune phase, and the chronic cardiac remodeling phase. Although individualized therapy should be applied depending on the phase, no clinical or experimental studies have found biomarkers that distinguish between the 3 phases. Theiler’s murine encephalomyelitis virus belongs to the genus Cardiovirus and can cause myocarditis in susceptible mouse strains. Methods and Results Using this novel model for viral myocarditis induced with Theiler’s murine encephalomyelitis virus, we conducted multivariate analysis including echocardiography, serum troponin and viral RNA titration, and microarray to identify the biomarker candidates that can discriminate the 3 phases. Using C3H mice infected with Theiler’s murine encephalomyelitis virus on 4, 7, and 60 days post infection, we conducted bioinformatics analyses, including principal component analysis and k-means clustering of microarray data, because our traditional cardiac and serum assays, including 2-way comparison of microarray data, did not lead to the identification of a single biomarker. Principal component analysis separated heart samples clearly between the groups of 4, 7, and 60 days post infection. Representative genes contributing to the separation were as follows: 4 and 7 days post infection, innate immunity–related genes, such as Irf7 and Cxcl9; 7 and 60 days post infection, acquired immunity–related genes, such as Cd3g and H2-Aa; and cardiac remodeling–related genes, such as Mmp12 and Gpnmb. Conclusions Sets of molecules, not single molecules, identified by unsupervised principal component analysis, were found to be useful as phase-specific biomarkers.

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“…SPP1 is a member of the osteopontin superfamily. It functions as a cytokine that regulates the expression of the M1-associated cytokines, interferon-γ and interleukin-12, in the peripheral immune system (Santamaria and Corral, 2013). It has been associated with microglia upregulation following transient forebrain ischemia (Choi et al, 2007), in a subset of amoeboid microglia in the hippocampus following kainic acid induced injury (Kim et al, 2002), and in peri-arterial areas following TMT (Morita et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Molecular Markers for Pro-inflammatory Cytokine M1 Stage and Resident Microglia in Trimethyltin-Induced Hippocampal Injury

2013

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Microglia polarization to the classical M1 activation state is characterized by elevated pro-inflammatory cytokines; however, a full profile has not been generated in the early stages of a sterile inflammatory response recruiting only resident microglia. We characterized the initial M1 state in a hippocampal injury model dependent upon tumor necrosis factor (TNF) receptor signaling for dentate granule cell death. Twenty-one-day-old CD1 male mice were injected with trimethyltin (TMT 2.3 mg/kg, i.p.) and the hippocampus was examined at an early stage (24-h post-dosing) of neuronal death. Glia activation was assessed using a custom quantitative nuclease protection assay (qNPA). We report elevated mRNA levels for glia response such as ionizing calcium-binding adapter molecule-1 and glial fibrillary acidic protein, (Gfap); Fas, hypoxia inducible factor alpha, complement component 1qb, TNF-related genes (Tnf, Tnfaip3, Tnfrsfla); interleukin -1 alpha, Cd44, chemokine (C-C motif) ligand (Ccl)2, Cc14, integrin alpha M, lipocalin (Lcn2), and secreted phosphoprotein 1 (Spp1). These changes occurred in the absence of changes in matrix metalloproteinase 9 and 12, neural cell adhesion molecule, metabotropic glutamate receptor (Grm)3, and Ly6/neurotoxin 1 (Lynx1), as well as, a decrease in neurotrophin 3, glutamate receptor subunit epsilon (Grin)-2b, and neurotrophic tyrosine kinase receptor, type 3. The M2 anti-inflammatory marker, transforming growth factor beta-1 (Tgfb1) was elevated. mRNAs associated with early stage of injury-induced neurogenesis including fibroblast growth factor 21 and Mki67 were elevated. In the “non-injured” temporal cortex receiving projections from the hippocampus, Lynx1, Grm3, and Grin2b were decreased and Gfap increased. Formalin fixed-paraffin-embedded tissue did not generate a comparable profile.

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Osteopontin-dependent regulation of Th1 and Th17 cytokine responses in Trypanosoma cruzi-infected C57BL/6 mice

Cited by 22 publications

References 43 publications

Dual regulation of osteopontin production by TLR stimulation in dendritic cells

Dual regulation of osteopontin production by TLR stimulation in dendritic cells

Bioinformatics Multivariate Analysis Determined a Set of Phase-Specific Biomarker Candidates in a Novel Mouse Model for Viral Myocarditis

In Vivo Molecular Markers for Pro-inflammatory Cytokine M1 Stage and Resident Microglia in Trimethyltin-Induced Hippocampal Injury

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