Remission of chronic fungal asthma in the absence of CCR8

doi:10.1016/j.jaci.2006.12.660

Journal of Allergy and Clinical Immunology

Volume 119, Issue 4, April 2007, Pages 997-1004

https://doi.org/10.1016/j.jaci.2006.12.660 Get rights and content

Background

Experimental studies have generated conflicting data regarding the role of CCR8 in antigen-driven allergic airway disease models, thereby dampening enthusiasm for further exploration of the targeting of CCR8 in asthma.

Objective

Recent data show that the absence of CCR8 leads to a marked amplification of the innate immune response, and these data provided impetus for the current study, which addressed the role of this chemokine receptor in a model of fungal asthma.

Methods

Wild-type (CCR8^+/+) and CCR8-deficient (CCR8^−/−) mice were sensitized to Aspergillus fumigatus antigens and challenged via intra-tracheal injection with live fungal conidia, and parameters of airway hyperresponsiveness, inflammation, and remodeling were examined.

Results

At day 7 after conidia challenge in wild-type (CCR8^+/+) and CCR8-deficient (CCR8^−/−) mice sensitized to A fumigatus antigens, markedly less fungal material was present in the lungs of the CCR8^−/− group compared with the CCR8^+/+ group. At day 14 after conidia challenge, all characteristic airway physiology, inflammatory, and remodeling parameters of fungal asthma were significantly decreased or abolished in the CCR8^−/− group relative to the CCR8^+/+ group.

Conclusion

Together these data show that an enhanced innate immune response in the absence of CCR8 promotes the rapid clearance of fungal material from the lung, thereby facilitating the remission of fungal asthma.

Clinical implications

This study shows that the clearance of fungal material from the lung was enhanced in the absence of CCR8, which suggests that this receptor may be an attractive target in fungal-allergic asthma and other fungal-associated pulmonary diseases.

Section snippets

Mice

CCR8^−/− mice were generated as described previously and bred under specific-pathogen free (SPF) conditions.¹⁴ The lack of CCR8 transcripts in these mice was confirmed by real-time polymerase chain reaction (RT-PCR) (not shown) and quantitative PCR analysis (Fig 1, G). Age-matched and sex-matched, SPF C57BL/6 (CCR8^+/+) mice were purchased from Taconic (Hudson, NY) and maintained in an SPF facility. Committee approval for this study was obtained from the University of Michigan Medical School.

Chronic fungal asthma model and time point data collection

Divergence of whole lung cytokine and chemokine levels in CCR8^−/− mice at day 3

At day 3 after conidia challenge, histologic evidence of pulmonary inflammation was similar in both CCR8^+/+ and CCR8^−/− mice (Fig 1, A and B, and data not shown). Systemic features of allergic disease were also similarly evident in CCR8^+/+ and CCR8^−/− mice, including similarly elevated total serum IgE and IgG2A (Fig 1, C). Enumeration of the leukocytes retrieved from BAL did not reveal any significant differences in the cellularity of the alveolar compartment in these mice at day 3 (Fig 1, D).

Discussion

Asthma is characterized by AHR, chronic inflammation of the airways, reversible airways obstruction, and airways remodeling.²⁰ The chronicity of this lung disease seems to be, in part, caused by repeated exposure to specific environmental allergens such as insect byproducts, animal danders, and fungi such as A fumigatus.21, 22, 23 In the current study, we employed a model of fungal asthma initiated by a live conidial challenge in A fumigatus–sensitized mice, to examine the immunologic

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Supported by National Institutes of Health Research Grant HL069865 (to C.M.H.).

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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Basic and clinical immunologyRemission of chronic fungal asthma in the absence of CCR8

Background

Objective

Methods

Results

Conclusion

Clinical implications

Section snippets

Mice

Chronic fungal asthma model and time point data collection

Divergence of whole lung cytokine and chemokine levels in CCR8−/− mice at day 3

Discussion

Curr Opin Pharmacol

Trends Pharmacol Sci

J Biol Chem

Blood

Blood

Am J Pathol

Blood

Blood

Microbes Infect

Identification of CCR8 as the specific receptor for the human beta-chemokine I-309: cloning and molecular characterization of murine CCR8 as the receptor for TCA-3

J Immunol

Identification of CCR8: a human monocyte and thymus receptor for the CC chemokine I-309

J Exp Med

Human CC chemokine liver-expressed chemokine/CCL16 is a functional ligand for CCR1, CCR2 and CCR5, and constitutively expressed by hepatocytes

Int Immunol

The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells

J Immunol

The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics

J Clin Invest

Increased responsiveness of murine eosinophils to MIP-1beta (CCL4) and TCA-3 (CCL1) is mediated by their specific receptors, CCR5 and CCR8

J Leukoc Biol

Expression and characterization of TCA3: a murine inflammatory protein

J Immunol

CC chemokine ligand 1 promotes recruitment of eosinophils but not Th2 cells during the development of allergic airways disease

J Immunol

Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice

J Exp Med

CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease

J Immunol

Basic and clinical immunology
Remission of chronic fungal asthma in the absence of CCR8

Divergence of whole lung cytokine and chemokine levels in CCR8^−/− mice at day 3