Differential Expression of Chemokines in Patients with Localized and Diffuse Cutaneous American Leishmaniasis

Ritter, Uwe; Moll, Heidrun; Laskay, Tamás; Bröcker, Eva‐Bettina; Velazco, Oscar; Becker, Ingeborg; Gillitzer, R.

doi:10.1093/infdis/173.3.699

Cited by 108 publications

(121 citation statements)

References 36 publications

Supporting

Mentioning

112

Contrasting

Order By: Relevance

“…For example, patients suffering from cutaneous leishmaniasis show a significant increase in levels of MCP-1 and MIP-1a mRNA in their lesions [34]. Similarly, infection of mouse and human macrophages with L. major promastigotes induces expression of several chemokines such as MCP-1, IL-8, and MCAF [35][36][37].…”

Section: Resultsmentioning

confidence: 99%

“…These findings demonstrate that CXCR3 plays a crucial role in the host defense against L. major by regulating the immune response required for controlling parasite growth at the site of infection. Several studies have implicated a role for chemokines in regulation of the immune response during Leishmania infection [34][35][36][37][38][39][40][41]. For example, patients suffering from cutaneous leishmaniasis show a significant increase in levels of MCP-1 and MIP-1a mRNA in their lesions [34].…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2005

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

show abstract

“…This complement activation, among an array of other factors, creates a C5a gradient along which macrophages are chemotactically attracted [36]. Furthermore, differential expressions of chemokines such as macrophage chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1a and -1b, RANTES (Regulated on Activation, Normal T cell Expressed and presumably Secreted), I-309, interleukin (IL)-8, and adhesion molecules, have been reported in American cutaneous leishmaniasis [37,38]. The chemotaxis could also occur through continuous synthesis by living promastigotes of a cell membrane-associated factor(s), because promastigote culture supernatant failed to modulate the macrophage migration, indicating that the factor(s) responsible for chemotaxis is not released into the surrounding medium.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Leishmania major Promastigote‐Induced Macrophage Migration is Modulated by Sensory and Autonomic Neuropeptides

et al. 1998

View full text Add to dashboard Cite

Ahmed AA, Wahbi A, Nordlind K, Kharazmi A, Sundqvist K-G, Mutt V, Lidén S. In Vitro Leishmania major Promastigote-Induced Macrophage Migration is Modulated by Sensory and Autonomic Neuropeptides. Scand J Immunol 1998;48:79-85 Recruitment, migration and adherence of macrophages and their interaction with inoculated promastigotes are key steps in the initiation of the inflammatory process in cutaneous leishmaniasis. Parasite-and nervous system-derived factors might be involved in this process. In the present study the chemotactic activities of live, killed and sonicated Leishmania major promastigotes and of the promastigote culture supernatant as well as the L. major surface protease gp63 towards a murine macrophage cell line, Raw 264.7, were investigated, using the Boyden technique. The sensory neuropeptides SOM, CGRP and SP, and the autonomic neuropeptides VIP and NPY, were also investigated for possible modulatory effects on this chemotaxis, using the living promastigotes. Living promastigotes were the most efficient attractants for macrophages compared with other forms of the parasites. Prior incubation of the macrophages with the parasites completely abolished the chemotactic activity. This might indicate that the living promastigote chemotaxis is a receptor-mediated process. On the other hand, paraformaldehyde-killed promastigotes not only failed to induce macrophage chemotaxis but also inhibited it in comparison with the control. The surface protease gp63 tended to inhibit the macrophage chemotactic activity and the sonicate tended to stimulate it compared with controls. The culture supernatant had no effect, indicating that the chemoattractive factors putatively synthesized by the living promastigotes are not released to the surrounding medium. Somatostatin inhibited L. major promastigoteinduced macrophage migration at a high concentration, 10 ¹6 M, while substance P inhibited it at both low concentrations, 10 ¹10 and 10 ¹9 M, and a high one, 10 ¹6 M, the last-mentioned having the greatest inhibitory effect. A stimulatory effect of calcitonin gene-related peptide was found at high concentrations, 10 ¹5 and 10 ¹6 M. Vasoactive intestinal peptide stimulated macrophage chemotactic activity at both a high, 10 ¹5 M, and at a low, 10 ¹9 M, concentration, the same concentration at which neuropeptide Y exerted its maximum inhibitory effect.

show abstract

“…For over a decade, Leishmania has been known to induce or inhibit the expression of chemokines to control recruitment of immune cells. In human cutaneous leishmaniasis, the diffuse form of the disease has been associated with lower levels of the macrophage chemotactic factor CCL2 (MCP-1), which is higher in the localized form of the disease (Ritter et al, 1996). Since CCL2 also induces antiparasitic activity in macrophages (Mannheimer, Hariprashad, Stoeckle, & Murray, 1996), inhibition of this chemokine by Leishmania could potentially facilitate its survival within the host.…”

Section: Mechanisms Of Immune Evasionmentioning

confidence: 99%

Mechanisms of Immune Evasion in Leishmaniasis

Gupta

Oghumu

Satoskar

2013

Advances in Applied Microbiology

206

150

View full text Add to dashboard Cite

Diseases caused by Leishmania present a worldwide problem, and current therapeutic approaches are unable to achieve a sterile cure. Leishmania is able to persist in host cells by evading or exploiting host immune mechanisms. A thorough understanding of these mechanisms could lead to better strategies for effective management of Leishmania infections. Current research has focused on parasite modification of host cell signaling pathways, entry into phagocytic cells, and modulation of cytokine and chemokine profiles that alter immune cell activation and trafficking to sites of infection. Immuno-therapeutic approaches that target these mechanisms of immune evasion by Leishmania offer promising areas for preclinical and clinical research.

show abstract

Differential Expression of Chemokines in Patients with Localized and Diffuse Cutaneous American Leishmaniasis

Cited by 108 publications

References 36 publications

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

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

In Vitro Leishmania major Promastigote‐Induced Macrophage Migration is Modulated by Sensory and Autonomic Neuropeptides

Mechanisms of Immune Evasion in Leishmaniasis

Contact Info

Product

Resources

About

Differential Expression of Chemokines in Patients with Localized and Diffuse Cutaneous American Leishmaniasis

Cited by 108 publications

References 36 publications

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

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

In Vitro Leishmania major Promastigote‐Induced Macrophage Migration is Modulated by Sensory and Autonomic Neuropeptides

Mechanisms of Immune Evasion in Leishmaniasis

Contact Info

Product

Resources

About

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

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