Early granuloma formation after aerosol <i>Mycobacterium tuberculosis</i> infection is regulated by neutrophils via CXCR3‐signaling chemokines

Seiler, Peter; Aichele, Peter; Bandermann, Silke; Hauser, Anja E.; Liu, Bao; Gerard, Norma P.; Gérard, Craig; Ehlers, Stefan; Mollenkopf, Hans-Joachim; Kaufmann, Stefan H. E.

doi:10.1002/eji.200323956

Cited by 217 publications

(192 citation statements)

References 59 publications

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“…The measurement of cellular infiltration in subsequent aspirates serves as a model in patients for the early infiltration to the region in primary infection. Neutrophils were the first cell type (also observed in the mouse model [37]), followed by macrophages. Lymphocytes formed the predominant cell type at later time points [21].…”

Section: The Immune Response In Progressive and Non-progressive Tubermentioning

confidence: 84%

New insights into the function of granulomas in human tuberculosis

Ulrichs

Kaufmann

2005

The Journal of Pathology

353

337

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The human tuberculous granuloma provides the morphological framework for local immune processes central to the outcome of tuberculosis. This review article describes investigations on human lung granulomas aimed at better understanding the regional host response and counter-measures to Mycobacterium tuberculosis. These findings lead to a revised view of the regional immune response in human tuberculosis. Novel insights into this dynamic cross-talk form the basis of novel intervention strategies.

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Section: The Immune Response In Progressive and Non-progressive Tubermentioning

confidence: 84%

New insights into the function of granulomas in human tuberculosis

Ulrichs

Kaufmann

2005

The Journal of Pathology

353

337

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“…In addition, extensive research has now clearly established that the release of chemokines and cytokines constitutes yet another key contribution of neutrophils to innate immunity (reviewed in reference [4]). Among the chemokines produced by neutrophils both in vitro and in vivo, CXCL10 stands out as being somewhat peculiar in terms of its induction characteristics, as originally shown by us [5,6] as well as by other groups [7][8][9]. Indeed, CXCL10 expression occurs in vitro only if However, the molecular bases of the particular inducibility of CXCL10 in human neutrophils have only been partially elucidated thus far.…”

Section: Introductionmentioning

confidence: 96%

Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

et al. 2007

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The CXCL10 chemokine is a critical chemoattractant for the recruitment of activated Th1 and NK cells into inflammatory sites. CXCL10 is typically produced by myeloid cells in response to IFN-c, as well as by neutrophils, though the latter require a costimulation with IFN-c and LPS. In this study, we investigated the molecular mechanism(s) whereby IFN-c and TLR4 ligation synergize to induce CXCL10 expression in neutrophils. By primary transcript real-time PCR analysis, we demonstrate that the CXCL10 gene is transcriptionally induced by the LPS plus IFN-c combination in neutrophils, consistent with previous studies showing that increased CXCL10 gene expression does not reflect enhanced mRNA stability. The IFN-c-induced STAT1 activation and the lipopolysaccharide (LPS)-induced NF-jB activation were not enhanced if neutrophils were exposed to both stimuli, whereas both transcription factors were activated by IFN-c or LPS in monocytes. Finally, pharmacological inhibitors of NF-jB demonstrated its role in the induction of CXCL10 expression by LPS plus IFN-c in neutrophils, and by LPS or IFN-c in monocytes. Together, these results suggest that in neutrophils, the synergy observed between LPS and IFN-c toward CXCL10 gene expression likely reflects the cooperative induction of the NF-jB and STAT1 transcription factors by LPS and IFN-c, respectively. IntroductionCXCL10/IFN-c-inducible protein 10 (IP-10) is a critical component of several immune responses, acting notably as a chemoattractant for activated NK and Th1 cells into sites of inflammation. CXCL10 mediates its various activities by binding to CXCR3 expressed on activated Th1 and NK cells [1], and influences the behavior of nonimmune cells that express a CXCR3. For instance, it inhibits endothelial cell proliferation through interfering with the function of receptors for the growth factors, basic fibroblast growth factor and vascular endothelial growth factor, resulting in the inhibition of angiogenesis [2].Neutrophils are cells of the innate immune system that play an essential role in antimicrobial defense via the release of numerous toxic mediators [3]. In addition, extensive research has now clearly established that the release of chemokines and cytokines constitutes yet another key contribution of neutrophils to innate immunity (reviewed in reference [4]). Among the chemokines produced by neutrophils both in vitro and in vivo, CXCL10 stands out as being somewhat peculiar in terms of its induction characteristics, as originally shown by us [5,6] as well as by other groups [7][8][9]. Indeed, CXCL10 expression occurs in vitro only if However, the molecular bases of the particular inducibility of CXCL10 in human neutrophils have only been partially elucidated thus far. In this regard, we have recently clarified that the reason explaining the inability of LPS to induce CXCL10 mRNA expression in neutrophils reflects the fact that in this cell type, LPS is unable to mobilize the intracellular MyD88-independent pathway upon TLR4 binding [11]. As a result, LPS fails to...

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“…Moreover, experimental studies using a cardiac transplantation model show that CXCR3 -/-recipients and anti-CXCR3 Ab-treated wildtype mice exhibit prolonged survival of a cardiac allograft associated with a marked decrease in recruitment of CD4 + and CD8 + T cells, but not macrophages, into the transplanted organ [26]. Moreover, recent studies have shown that CXCR3-signaling chemokines also regulate early granuloma formation by neutrophils following Mycobacterium tuberculosis infection [27] and eosinophil recruitment in early delayed-type hypersensitivity [28].Previous studies have shown that CD4 + Th1 cells preferentially express CCR5 and CXCR3, which may regulate migration of these cells into the site of inflammation [24,29,30]. Nevertheless, others have shown that CD4 + Th2 cells also express high levels of CXCR3 [31,32].…”

mentioning

confidence: 99%

CXCR3^–/– mice mount an efficient Th1 response but fail to control Leishmania major infection

et al. 2005

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Chemokines play a critical role in recruitment of leukocytes to the site of infection, which is essential for host defense. We analyzed the role of CXC chemokine receptor 3 (CXCR3) in the control of cutaneous leishmaniasis using CXCR3 -/-C57BL/6 mice. We found that Leishmania major-infected CXCR3 -/-mice mount an efficient Th1 response as evident by markedly increased serum levels of Th1-associated IgG2a and significant production of IFN-c and IL-12 by the draining lymph node cells, restrict systemic spread of infection, but fail to control parasite replication at the site of infection and develop chronic non-healing lesions. Furthermore, the inability of CXCR3 -/-mice to control cutaneous L. major growth was associated with fewer CD4 + and CD8 + T cells and significantly lower levels of IFN-c in their lesions as compared to CXCR3 +/+ mice. These results demonstrate that CXCR3 plays a critical role in the host defense against cutaneous leishmaniasis caused by L. major. Furthermore, they also suggest that the susceptibility of CXCR3 -/-mice to L. major is due to impaired CD4 + and CD8 + T cell trafficking and decreased production of IFN-c at the site of infection rather than to their inability to mount a parasite-specific Th1 response. IntroductionLeishmania species are obligate intracellular parasites that are of extensive public health importance in the tropical and subtropical regions of the world [1]. In humans, cutaneous leishmaniasis caused by Leishmania major commonly manifests as a self-healing skin lesion followed by the development of long-term immunity. Several studies have shown that an IL-12-driven Th1 response and IFN-c production are critical for the control of L. major infection in genetically resistant mice, such as CBA/J, C57BL/6, and C3H [2][3][4][5]. On the other hand, the development of non-healing lesions in susceptible BALB/c mice is associated with the preferential induction of a Th2-like response associated with production of 6].The chemokine superfamily comprises a large number of small soluble proteins that are involved in the development and homeostasis of the hematopoietic system, angiogenesis, tissue repair, and regulation of the host immune response [7,8]. Recent studies have shown that chemokines play a critical role in the development of innate as well as acquired immunity against a variety [18]. Three CXC chemokines, CXCL9 (Mig), CXCL10 (IFN-inducible protein 10, IP-10) and CXCL11 (IFN-inducible T cell alpha chemoattractant, I-TAC), signal via CXCR3 [19,20], activate Ras/extracellular signal-regulated kinase (ERK), Src, and the phosphatidylinositol 3-kinase/Akt pathway, and mediate their biological functions such as cell migration and proliferation [21]. Many clinical studies have implicated a role for CXCR3 in the pathogenesis of several inflammatory diseases such as multiple sclerosis, psoriasis, and rheumatoid arthritis by facilitating the recruitment of pathogenic T cells to the site of inflammation [22][23][24][25]. Moreover, experimental studies using a cardiac transplanta...

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Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3‐signaling chemokines

Cited by 217 publications

References 59 publications

New insights into the function of granulomas in human tuberculosis

New insights into the function of granulomas in human tuberculosis

Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

CXCR3^–/– mice mount an efficient Th1 response but fail to control Leishmania major infection

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Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3‐signaling chemokines

Cited by 217 publications

References 59 publications

New insights into the function of granulomas in human tuberculosis

New insights into the function of granulomas in human tuberculosis

Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

CXCR3–/– mice mount an efficient Th1 response but fail to control Leishmania major infection

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CXCR3^–/– mice mount an efficient Th1 response but fail to control Leishmania major infection