Eotaxin-3 (CCL26) exerts innate host defense activities that are modulated by mast cell proteases.
BACKGROUND
During bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities including β-defensins, ELR-negative CXC chemokines, and the cathelicidin LL-37. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation.


METHODS
Antibacterial activities of the eotaxins were investigated using viable count assays, electron microscopy, and methods assessing bacterial permeabilization. Fragments generated by mast cell proteases were characterized, and their potential antibacterial, receptor-activating, and lipopolysaccharide-neutralizing activities were investigated.


RESULTS
CCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens Streptococcus pneumoniae, Staphylococcus aureus, Nontypeable Haemophilus influenzae, and Pseudomonas aeruginosa. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2 -terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2 -terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2 -terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. None of the fragments activated the CCR3-receptor.


CONCLUSIONS
Taken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases.
Respiratory Medicine & Allergology, Lund University, Lund, Sweden.
A
A
Gela
G
G
Kasetty
S
S
Jovic
M
M
Ekoff
G
G
Nilsson
M
M
Mörgelin
S
S
Kjellström
J E
JE
Pease
A
A
Schmidtchen
A
A
Egesten
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D054413:Chemokine CCL11 / Q000378:metabolism / Q000494:pharmacology; D054423:Chemokine CCL24 / Q000378:metabolism / Q000494:pharmacology; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D008958:Models, Molecular; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D054397:Receptors, CCR3 / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000648:ultrastructure; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000648:ultrastructure
D000900:Anti-Bacterial Agents; C120429:CCL26 protein, human; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D054397:Receptors, CCR3; D010447:Peptide Hydrolases
allergy; bacterial infection; eotaxins; host defense