Activation of Phosphoinositide 3-Kinases by the CCR4 Ligand Macrophage-Derived Chemokine Is a Dispensable Signal for T Lymphocyte Chemotaxis

Cronshaw, Darran G.; Owen, Catherine; Brown, Zarin; Ward, Stephen G.

doi:10.4049/jimmunol.172.12.7761

Cited by 52 publications

(58 citation statements)

References 85 publications

(91 reference statements)

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“…4). CCL11 and IL-5 are potent inducers of eosinophil development and/or chemotaxis (15), while dendritic cell-produced CCL22 is increased in patients with allergic rhinitis or atopic dermatitis and induces Th2 chemotaxis (41)(42)(43). However, other cytokines might also play a role in the increased eosinophil recruitment and pathology observed in our study.…”

Section: Discussioncontrasting

confidence: 51%

Eosinophils Are Recruited in Response to Chitin Exposure and Enhance Th2-Mediated Immune Pathology in Aspergillus fumigatus Infection

O'Dea

Amarsaikhan

et al. 2014

Infect Immun

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In patients infected with the fungus Aspergillus fumigatus, Th1 responses are considered protective, while Th2 responses are associated with increased morbidity and mortality. How host-pathogen interactions influence the development of these protective or detrimental immune responses is not clear. We compared lung immune responses to conidia from two fungal isolates that expressed different levels of the fungal cell wall component chitin. We observed that repeated aspirations of the high-chitinexpressing isolate Af5517 induced increased airway eosinophilia in the lungs of recipient mice compared to the level of eosinophilia induced by isolate Af293. CD4؉ T cells in the bronchoalveolar lavage fluid (BALF) of Af5517-aspirated mice displayed decreased gamma interferon secretion and increased interleukin-4 transcription. In addition, repeated aspirations of Af5517 induced lung transcription of the Th2-associated chemokines CCL11 (eotaxin-1) and CCL22 (macrophage-derived chemokine). Eosinophil recruitment in response to conidial aspiration was correlated with the level of chitin exposure during germination and was decreased by constitutive lung chitinase expression. Moreover, eosinophil-deficient mice subjected to multiple aspirations of Af5517 prior to neutrophil depletion and infection exhibited decreased morbidity and fungal burden compared to the levels of morbidity and fungal burden found in wild-type mice. These results suggest that exposure of chitin in germinating conidia promotes eosinophil recruitment and ultimately induces Th2-skewed immune responses after repeated aspiration. Furthermore, our results suggest that eosinophils should be examined as a potential therapeutic target in patients that mount poorly protective Th2 responses to A. fumigatus infection.

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Section: Discussioncontrasting

confidence: 51%

Eosinophils Are Recruited in Response to Chitin Exposure and Enhance Th2-Mediated Immune Pathology in Aspergillus fumigatus Infection

O'Dea

Amarsaikhan

et al. 2014

Infect Immun

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“…Although the pathways involved in CCL17's effects remain to be elucidated, mechanisms inhibiting Jak/Stat signaling are well defined, e.g., dephosphorylation, proteolytic degradation, or association with inhibitory molecules (48). It is conceivable that CCL17 can interfere with Stat5 phosphorylation by inducing the MAPK pathway, as seen for CCL17-induced interference with Src kinase and ERK phosphorylation, or the PI3K pathway (49)(50)(51). Notably, the putative Stat-inducible gene c-fos was upregulated in T cells after exposure to Ccl17 E/E DCs (A. Zernecke et al, unpublished observations), supporting the hypothesis that CCL17 interacts with growth and differentiation processes through a Stat-dependent pathway.…”

Section: Discussionsupporting

confidence: 49%

CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice

Weber¹,

Meiler²,

Döring³

et al. 2011

J. Clin. Invest.

242

260

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Immune mechanisms are known to control the pathogenesis of atherosclerosis. However, the exact role of DCs, which are essential for priming of immune responses, remains elusive. We have shown here that the DC-derived chemokine CCL17 is present in advanced human and mouse atherosclerosis and that CCL17 + DCs accumulate in atherosclerotic lesions. In atherosclerosis-prone mice, Ccl17 deficiency entailed a reduction of atherosclerosis, which was dependent on Tregs. Expression of CCL17 by DCs limited the expansion of Tregs by restricting their maintenance and precipitated atherosclerosis in a mechanism conferred by T cells. Conversely, a blocking antibody specific for CCL17 expanded Tregs and reduced atheroprogression. Our data identify DC-derived CCL17 as a central regulator of Treg homeostasis, implicate DCs and their effector functions in atherogenesis, and suggest that CCL17 might be a target for vascular therapy.

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“…In lymphocytes, contradictory results have been obtained using PI3K inhibitors (Sotsios et al, 1999;Cronshaw et al, 2004). Moreover, it was recently shown that lymphocyte homing is controlled mainly by DOCK-2 activity, whereas PI3Kγ activation has a minor role in this process (Nombela-Arrieta et al, 2004;Ward, 2004).…”

Section: Discussionmentioning

confidence: 96%

PTEN regulates motility but not directionality during leukocyte chemotaxis

Lacalle

Gómez‐Moutón

Barber

et al. 2004

Journal of Cell Science

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The localization at opposite cell poles of phosphatidylinositol-3 kinases and PTEN (phosphatase and tensin homolog on chromosome 10) governs Dictyostelium chemotaxis. To study this model in mammalian cells, we analyzed the dynamic redistribution of green fluorescent protein (GFP)-tagged PTEN chimeras during chemotaxis. N- or C-terminus GFP-tagged PTEN was distributed homogenously in the cytoplasm of chemotaxing PTEN-negative Jurkat cells and PTEN-positive HL60 cells. Moreover, we did not detect uropod accumulation of endogenous PTEN in chemoattractant-stimulated HL60 cells. Cell fractionation indicated that both endogenous and ectopically expressed PTEN were confined largely to the cytosol, and that chemoattractant stimulation did not alter this location. PTEN re-expression in Jurkat cells or PTEN depletion by specific siRNA in HL60 cells did not affect cell gradient sensing; PTEN nonetheless modulated chemoattractant-induced actin polymerization and the speed of cell movement. The results suggest a role for PTEN in regulating actin polymerization, but not directionality during mammalian cell chemotaxis.

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Activation of Phosphoinositide 3-Kinases by the CCR4 Ligand Macrophage-Derived Chemokine Is a Dispensable Signal for T Lymphocyte Chemotaxis

Cited by 52 publications

References 85 publications

Eosinophils Are Recruited in Response to Chitin Exposure and Enhance Th2-Mediated Immune Pathology in Aspergillus fumigatus Infection

Eosinophils Are Recruited in Response to Chitin Exposure and Enhance Th2-Mediated Immune Pathology in Aspergillus fumigatus Infection

CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice

PTEN regulates motility but not directionality during leukocyte chemotaxis

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