Response to Comment on ''Nonhematopoietic
Cells Are Key Players in Innate Control of
Bacterial Airway Infection''
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J Immunol 2011; 186:5019-5020; ;
doi: 10.4049/jimmunol.1190014
http://www.jimmunol.org/content/186/9/5019.2
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References
Salomé LeibundGut-Landmann and Annette Oxenius
Comment on “Nonhematopoietic
Cells Are Key Players in Innate
Control of Bacterial Airway
Infection”
U
Samithamby Jeyaseelan
Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA
70803
Address correspondence and reprint requests to Dr. Samithamby Jeyaseelan, Department
of Pathobiological Sciences, Louisiana State University, Skip Bertman Drive, Baton
Rouge, LA 70803. E-mail address: [email protected]
References
1. LeibundGut-Landmann, S., K. Weidner, H. Hilbi, and A. Oxenius. 2011. Nonhematopoietic cells are key players in innate control of bacterial airway infection.
J. Immunol. 186: 3130–3137.
2. Balamayooran, G., S. Batra, M. B. Fessler, K. I. Happel, and S. Jeyaseelan. 2010.
Mechanisms of neutrophil accumulation in the lungs against bacteria. Am. J.
Respir. Cell Mol. Biol. 43: 5–16.
Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1190013
Response to Comment on
“Nonhematopoietic Cells Are Key
Players in Innate Control of
Bacterial Airway Infection”
N
onhematopoietic cells in the lung play a nonredundant role in cross-talk with alveolar macrophages, facilitating early recruitment of neutrophil
granulocytes to the lung in response to experimental airway
infection with the Gram-negative bacterium Legionella pneumophila, the causative agent of Legionnaire’s disease. Our data
certainly do not question an equally important role of nonhematopoietic cells, in particular with alveolar macrophages
being the key sensors of L. pneumophila infection and, as such,
providing the initiating spark of the inflammatory response.
An essential component of this cross-talk is the MyD88dependent production of IL-1b by alveolar macrophages,
which is subsequently sensed by nonhematopoietic cells. In
support of the importance of the hematopoietic cell compartment in L. pneumophila control, bone marrow chimeric
mice with selective deletion of the TLR and IL-1R/IL-18R
signaling adaptor MyD88 in the hematopoietic compartment
also exhibited impaired control of L. pneumophila infection
(1), as did mice with selective MyD88 deletion in the nonhematopoietic compartment.
Neutrophil recruitment to sites of infection is guided by
several chemokines that signal through CXCR2. Because we focused our neutrophil-recruiting chemokine expression analysis
on CXCL1 and CXCL2, we cannot make any statements
about LIX and lungkine expression in our experimental system.
However, ablation of IL-1R signaling on nonhematopoietic
cells resulted in strongly impaired CXCL1 and CXCL2 production during the first hours postinfection, and this was
associated with severely impaired early neutrophil recruitment.
Furthermore, comparison of in vitro CXCL1 production
capacities of bone marrow-derived macrophages and alveolar
type I epithelial cells revealed that the latter produced about
one order of magnitude more CXCL1 than did the former
(S. LeibundGut-Landmann, K. Weidner, and A. Oxenius,
unpublished observations). Thus, although both hemato-
Downloaded from http://www.jimmunol.org/ by guest on July 28, 2017
sing bone marrow chimeras, LeibundGut-Landmann
et al. conclude in a recent study that nonhematopoietic cells are important to host defense in
the lung against an intracellular pathogen, Legionella pneumophila (reviewed in Ref. 1). Neutrophils are a critical contributor to host defense in the lungs (2) because selective
depletion of neutrophils results in substantial reduction in
the clearance of Klebsiella pneumoniae and L. pneumophila
organisms. Using bone marrow chimeras, we have shown that
both hematopoietic and nonhematopoietic cells in the lungs
are essential for neutrophil-dependent host defense against
extracellular pathogens, including Escherichia coli (3) and K.
pneumoniae (4). CXCL1/KC, CXCL2/MIP-2, CXCL5/LIX,
and lungkine are the primary neutrophil chemokines in mice,
and the receptor for these chemokines, CXCR2, is expressed
on both hematopoietic and nonhematopoietic cells. KC
and MIP-2 are produced by both hematopoietic and nonhematopoietic cells in the lung (2), whereas LIX and lungkine
are secreted primarily by nonhematopoietic cells, such as epithelial cells (5, 6). Although the reported findings (1) are conclusive, neutrophil accumulation was measured within 28 h
following infection and epithelial chemokines have not been
measured. Nonetheless, these findings (1) lead us to wonder
whether both hematopoietic and nonhematopoietic cells are
important for neutrophil-dependent host defense to extracellular Gram-negative pathogens, or whether one of these cell
types is necessary and/or sufficient to induce host defense
against intracellular Gram-negative pathogens. These findings
will have translational implications for harnessing innate
immunity versus targeting the causative bacterium to combat
multidrug-resistant bacteria and to develop potent vaccines
against pulmonary infections.
3. Cai, S., R. L. Zemans, S. K. Young, G. S. Worthen, and S. Jeyaseelan. 2009.
Myeloid differentiation protein-2-dependent and -independent neutrophil accumulation during Escherichia coli pneumonia. Am. J. Respir. Cell Mol. Biol. 40:
701–709.
4. Cai, S., S. Batra, S. A. Lira, J. K. Kolls, and S. Jeyaseelan. 2010. CXCL1 regulates
pulmonary host defense to Klebsiella infection via CXCL2, CXCL5, NF-kappaB,
and MAPKs. J. Immunol. 185: 6214–6225.
5. Jeyaseelan, S., R. Manzer, S. K. Young, M. Yamamoto, S. Akira, R. J. Mason, and
G. S. Worthen. 2005. Induction of CXCL5 during inflammation in the rodent lung
involves activation of alveolar epithelium. Am. J. Respir. Cell Mol. Biol. 32: 531–
539.
6. Rossi, D. L., S. D. Hurst, Y. Xu, W. Wang, S. Menon, R. L. Coffman, and
A. Zlotnik. 1999. Lungkine, a novel CXC chemokine, specifically expressed by
lung bronchoepithelial cells. J. Immunol. 162: 5490–5497.
5020
poietic and nonhematopoietic cells have the capacity to produce
CXCL1 and CXCL2 (2, 3), our data support a more prominent in vivo role of nonhematopoietic cells, at least during the
very early phase of experimental L. pneumophila infection.
Thus, nonhematopoietic cells are—at least in experimental
L. pneumophila infection—amplifiers of the tempo of very
early inflammatory responses by sensing inflammatory cues
conveyed by L. pneumophila-infected macrophages, which
they readily translate in enhanced neutrophil attraction and
improved pathogen control.
Salomé LeibundGut-Landmann and Annette Oxenius
Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich,
Switzerland
LETTERS TO THE EDITOR
Address correspondence and reprint requests to Dr. Annette Oxenius, Institute of
Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, HCI G401, 8093 Zurich,
Switzerland. E-mail address: [email protected]
References
1. Archer, K. A., F. Ader, K. S. Kobayashi, R. A. Flavell, and C. R. Roy. 2010.
Cooperation between multiple microbial pattern recognition systems is important
for host protection against the intracellular pathogen Legionella pneumophila.
Infect. Immun. 78: 2477–2487.
2. De Filippo, K., R. B. Henderson, M. Laschinger, and N. Hogg. 2008. Neutrophil
chemokines KC and macrophage-inflammatory protein-2 are newly synthesized
by tissue macrophages using distinct TLR signaling pathways. J. Immunol. 180:
4308–4315.
3. Cai, S., S. Batra, S. A. Lira, J. K. Kolls, and S. Jeyaseelan. 2010. CXCL1 regulates
pulmonary host defense to Klebsiella infection via CXCL2, CXCL5, NF-kappaB,
and MAPKs. J. Immunol. 185: 6214–6225.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1190014
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