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Leukocyte attraction by CCL20 and its receptor CCR6 in humans and mice with pneumococcal meningitis.

Klein M, Brouwer MC, Angele B, Geldhoff M, Marquez G, Varona R, Häcker G, Schmetzer H, Häcker H, Hammerschmidt S, van der Ende A, Pfister HW, van de Beek D, Koedel U - PLoS ONE (2014)

Bottom Line: CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts.The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers.Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

ABSTRACT
We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment.

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CCR6-deficient mice suffer from increased brain edema after antibiotic therapy.(A) Infected mice with CCR6-deficiency developed more pronounced brain edema than infected wild type mice 48 h after infection, reflected in an increase in the estimated brain volume. (B) At the same time point, an increase of brain albumin content was noted in infected Ccr6−/− mice, indicating blood-brain barrier disruption. These differences were only seen after but not before initiation of antibiotic therapy (24 h after infection). (C–G) Intracranial bleeding was similar in infected Ccr6−/− and wild type mice. (*) p<0.05 compared with WT control animals. Number of animals: 24 h: Ccr6−/− n = 12, WT n = 12; 48 h: Ccr6−/− n = 12, WT n = 13.
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pone-0093057-g005: CCR6-deficient mice suffer from increased brain edema after antibiotic therapy.(A) Infected mice with CCR6-deficiency developed more pronounced brain edema than infected wild type mice 48 h after infection, reflected in an increase in the estimated brain volume. (B) At the same time point, an increase of brain albumin content was noted in infected Ccr6−/− mice, indicating blood-brain barrier disruption. These differences were only seen after but not before initiation of antibiotic therapy (24 h after infection). (C–G) Intracranial bleeding was similar in infected Ccr6−/− and wild type mice. (*) p<0.05 compared with WT control animals. Number of animals: 24 h: Ccr6−/− n = 12, WT n = 12; 48 h: Ccr6−/− n = 12, WT n = 13.

Mentions: CCR6 is the only currently known receptor for CCL20. Ccr6−/− mice developed more severe disease than WT control animals reflected by higher clinical scores 24 h after infection (Figure 4A) and increased mortality 48 h after infection (Figure 4B). 24 h after infection, Ccr6−/− mice had lower CSF-WBC counts (Figure 4C,) and increased bacterial titers in the brain (Figure 4D). Brain IL-6, IL-1β, and MIP-2 levels of Ccr6−/− mice and WT mice were similar at 24 h (data not shown). At 48 h after infection, Ccr6−/− mice had lower CSF-WBC counts (Figure 4C), but increased brain volumes (Figure 5A) and an increased blood-brain barrier breakdown (Figure 5B) compared to infected WT mice. At 48 h after infection, bacterial titers (Figure 4D) and the number of cerebral bleedings in Ccr6−/− and WT mice were similar (Figure 5 C–F). In summary, Ccr6−/− mice suffering from meningitis were affected more strongly than wild type mice, as evidenced by an increase in clinical score and increased mortality.


Leukocyte attraction by CCL20 and its receptor CCR6 in humans and mice with pneumococcal meningitis.

Klein M, Brouwer MC, Angele B, Geldhoff M, Marquez G, Varona R, Häcker G, Schmetzer H, Häcker H, Hammerschmidt S, van der Ende A, Pfister HW, van de Beek D, Koedel U - PLoS ONE (2014)

CCR6-deficient mice suffer from increased brain edema after antibiotic therapy.(A) Infected mice with CCR6-deficiency developed more pronounced brain edema than infected wild type mice 48 h after infection, reflected in an increase in the estimated brain volume. (B) At the same time point, an increase of brain albumin content was noted in infected Ccr6−/− mice, indicating blood-brain barrier disruption. These differences were only seen after but not before initiation of antibiotic therapy (24 h after infection). (C–G) Intracranial bleeding was similar in infected Ccr6−/− and wild type mice. (*) p<0.05 compared with WT control animals. Number of animals: 24 h: Ccr6−/− n = 12, WT n = 12; 48 h: Ccr6−/− n = 12, WT n = 13.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974727&req=5

pone-0093057-g005: CCR6-deficient mice suffer from increased brain edema after antibiotic therapy.(A) Infected mice with CCR6-deficiency developed more pronounced brain edema than infected wild type mice 48 h after infection, reflected in an increase in the estimated brain volume. (B) At the same time point, an increase of brain albumin content was noted in infected Ccr6−/− mice, indicating blood-brain barrier disruption. These differences were only seen after but not before initiation of antibiotic therapy (24 h after infection). (C–G) Intracranial bleeding was similar in infected Ccr6−/− and wild type mice. (*) p<0.05 compared with WT control animals. Number of animals: 24 h: Ccr6−/− n = 12, WT n = 12; 48 h: Ccr6−/− n = 12, WT n = 13.
Mentions: CCR6 is the only currently known receptor for CCL20. Ccr6−/− mice developed more severe disease than WT control animals reflected by higher clinical scores 24 h after infection (Figure 4A) and increased mortality 48 h after infection (Figure 4B). 24 h after infection, Ccr6−/− mice had lower CSF-WBC counts (Figure 4C,) and increased bacterial titers in the brain (Figure 4D). Brain IL-6, IL-1β, and MIP-2 levels of Ccr6−/− mice and WT mice were similar at 24 h (data not shown). At 48 h after infection, Ccr6−/− mice had lower CSF-WBC counts (Figure 4C), but increased brain volumes (Figure 5A) and an increased blood-brain barrier breakdown (Figure 5B) compared to infected WT mice. At 48 h after infection, bacterial titers (Figure 4D) and the number of cerebral bleedings in Ccr6−/− and WT mice were similar (Figure 5 C–F). In summary, Ccr6−/− mice suffering from meningitis were affected more strongly than wild type mice, as evidenced by an increase in clinical score and increased mortality.

Bottom Line: CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts.The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers.Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

ABSTRACT
We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment.

Show MeSH
Related in: MedlinePlus