Production of CCL2 by Central Nervous System Cells Regulates Development of Murine Experimental Autoimmune Encephalomyelitis through the Recruitment of TNF- and iNOS-Expressing Macrophages and Myeloid Dendritic Cells

Dogan, Rukiye-Nazan E.; Elhofy, Adam; Karpus, William J.

doi:10.4049/jimmunol.180.11.7376

Cited by 86 publications

(91 citation statements)

References 68 publications

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“…In this experimental setting, the negative impact of CCL2/CCR2 ablation on the therapeutic activity of doxorubicin correlated with a reduced intratumoral recruitment of dendritic cell-like APCs. It should be noted that the CCL2/CCR2 system mediates the accumulation of myeloid-derived dendritic cells during allergic (27) and autoimmune inflammation (28), as well as at sites of parasitic (29), fungal (30), and mycobacterial infection (31). Thus, the inhibition of the CCL2/CCR2 signaling axis may blunt a wide range of inflammatory and immune reactions, including those required for the control of infectious pathogens and (pre)malignant cells.…”

Section: Discussionmentioning

confidence: 99%

CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

et al. 2014

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The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell-and T-lymphocyte-dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11bpresenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen-specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2 À/À mice failed to accumulate dendritic cell-like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. Cancer Res; 74(2); 436-45. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

et al. 2014

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“…BM reconstitution was performed as described previously with minor modifications (37). In brief, 3 × 10 6 mixed BM cells of CD45.1 WT and CD45.2 WT (1:1) or CD45.1 WT and CD45.2 Taci −/− (1:1) origins were injected i.v.…”

Section: Methodsmentioning

confidence: 99%

Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival

Lam

2012

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in TNFRSF13B, better known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), contribute to common variable immunodeficiency and autoimmunity in humans. How TACI regulates these two opposing conditions is unclear, however. TACI binds the cytokines BAFF and APRIL, and previous studies using gene KO mice indicated that loss of TACI affected only T-cell-independent antibody responses. Here we demonstrate that Taci −/− mice have expanded populations of T follicular helper (T fh ) and germinal center (GC) B cells in their spleens when immunized with T-cell-dependent antigen. The increased numbers of T fh and GC B cells in Taci −/− mice are largely a result of up-regulation of inducible costimulator (ICOS) ligand on TACI-deficient B cells, given that ablation of one copy of the Icosl allele restores normal levels of T fh and GC B cells in Taci −/− mice. Interestingly, despite the presence of increased T fh and antigenspecific B cells, immunized Taci −/− mice demonstrate defective antigen-specific antibody responses resulting from significantly reduced numbers of antibody-secreting cells (ASCs). This effect is attributed to the failure to down-regulate the proapoptotic molecule BIM in Taci −/− plasma cells. Ablation of BIM could rescue ASC formation in Taci −/− mice, suggesting that TACI is more important for the survival of plasma cells than for the differentiation of these cells. Thus, our data reveal dual roles for TACI in B-cell terminal differentiation. On one hand, TACI modulates ICOS ligand expression and thereby limits the size of T fh and GC B-cell compartments and prevents autoimmunity. On the other hand, it regulates the survival of ASCs and plays an important role in humoral immunity.costimulation | T-cell-dependent humoral immunity | TNF receptor T ransmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI/TNFRSF13B), B-cell activating factor (BAFF) receptor (BAFF-R/TNFRSF13C), and B-cell maturation antigen (BCMA/TNFRSF17) are closely related members of the TNF receptor superfamily and bind B-cell survival cytokines BAFF and APRIL (1). Although BAFF-R and BCMA have been shown to mediate the survival of follicular B cells (2) and plasma cells (3), respectively, a similar role for TACI in mediating the survival of B lymphocytes at any particular stage of B-cell differentiation has not been demonstrated definitively.However, mutations in TACI are thought to contribute to ∼10% of common variable immunodeficiency (CVID) in humans (4, 5). This syndrome is characterized by antibody deficiency in late childhood and early adulthood. Paradoxically, some patients with TACI-mutated CVID also develop autoimmune diseases (6). How TACI deficiency leads to antibody deficiencies on one hand and autoimmunity on the other hand is not well understood.Mice lacking TACI have been generated (7,8), and initial characterizations of these mice revealed modest phenotypes. Taci −/− mice had increased numbers of B cells but exhibited decreased antibody respons...

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“…Increased levels of neutrophil-and macrophage/monocyteattracting chemokines in the CRB and BS in LysMCre-SOCS3 fl//fl mice with atypical EAE CXCL1, CXCL2, and CCL2 are potent neutrophil and macrophage chemoattractants (8,37,38). Given the increased levels of neutrophils and macrophages/monocytes infiltrating into the CRB and BS in LysMCre-SOCS3 fl//fl mice with atypical EAE compared with SOCS3…”

Section: Neutrophil Infiltration Into the Crb And Bs Is Prominent In mentioning

confidence: 99%

Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

Liu

Holdbrooks

Meares

et al. 2015

The Journal of Immunology

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The JAK/STAT pathway is critical for development, regulation, and termination of immune responses, and dysregulation of the JAK/STAT pathway, that is, hyperactivation, has pathological implications in autoimmune and neuroinflammatory diseases. Suppressor of cytokine signaling 3 (SOCS3) regulates STAT3 activation in response to cytokines that play important roles in the pathogenesis of neuroinflammatory diseases, including IL-6 and IL-23. We previously demonstrated that myeloid lineage-specific deletion of SOCS3 resulted in a severe, nonresolving atypical form of experimental autoimmune encephalomyelitis (EAE), characterized by lesions, inflammatory infiltrates, elevated STAT activation, and elevated cytokine and chemokine expression in the cerebellum. Clinically, these mice exhibit ataxia and tremors. In this study, we provide a detailed analysis of this model, demonstrating that the atypical EAE observed in LysMCre-SOCS3 fl/fl mice is characterized by extensive neutrophil infiltration into the cerebellum and brainstem, increased inducible NO synthase levels in the cerebellum and brainstem, and prominent axonal damage. Importantly, infiltrating SOCS3-deficient neutrophils produce high levels of CXCL2, CCL2, CXCL10, NO, TNF-a, and IL-1b. Kinetic studies demonstrate that neutrophil infiltration into the cerebellum and brainstem of LysMCre-SOCS3 fl/fl mice closely correlates with atypical EAE clinical symptoms. Ab-mediated depletion of neutrophils converts the atypical phenotype to the classical EAE phenotype and, in some cases, a mixed atypical/classical phenotype. Blocking CXCR2 signaling ameliorates atypical EAE development by reducing neutrophil infiltration into the cerebellum/brainstem. Thus, neutrophils lacking SOCS3 display elevated STAT3 activation and expression of proinflammatory mediators and play a critical role in the development of atypical EAE.

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Production of CCL2 by Central Nervous System Cells Regulates Development of Murine Experimental Autoimmune Encephalomyelitis through the Recruitment of TNF- and iNOS-Expressing Macrophages and Myeloid Dendritic Cells

Cited by 86 publications

References 68 publications

CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival

Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

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