Published online
doi:10.1084/jem.20061232
The Journal of Experimental Medicine, Vol. 203, No. 13, 2907-2917
The Rockefeller University Press, 0022-1007 $30.00
© Xu et al.
Neutrophil histamine contributes to inflammation in mycoplasma pneumonia
Xiang Xu1,
Dongji Zhang2,
Hong Zhang3,
Paul J. Wolters1,4,
Nigel P. Killeen2,
Brandon M. Sullivan2,
Richard M. Locksley2,4,5,
Clifford A. Lowell3, and
George H. Caughey1,4,6,7
1 Cardiovascular Research Institute, 2 Department of Microbiology/Immunology, 3 Department of Laboratory Medicine,
4 Department of Medicine, and 5 Howard Hughes Medical Institute, University of California at San Francisco, San Francisco CA 94143
6 Veterans Affairs Medical Center, San Francisco, CA 94121
7 Northern California Institute for Research and Education, San Francisco, CA 94121
CORRESPONDENCE George H. Caughey: George.Caughey{at}ucsf.edu
Mycoplasmas cause chronic inflammation and are implicated in asthma. Mast cells defend against mycoplasma infection and worsen allergic inflammation, which is mediated partly by histamine. To address the hypothesis that mycoplasma provokes histamine release, we exposed mice to Mycoplasma pulmonis, comparing responses in wild-type and mast cell–deficient KitW-sh/KitW-sh (W-sh) mice. Low histamine levels in uninfected W-sh mice confirmed the conventional wisdom that mast cells are principal sources of airway and serum histamine. Although mycoplasma did not release histamine acutely in wild-type airways, levels rose up to 50-fold above baseline 1 week after infection in mice heavily burdened with neutrophils. Surprisingly, histamine levels also rose profoundly in infected W-sh lungs, increasing in parallel with neutrophils and declining with neutrophil depletion. Furthermore, neutrophils from infected airway were highly enriched in histamine compared with naive neutrophils. In vitro, mycoplasma directly stimulated histamine production by naive neutrophils and strongly upregulated mRNA encoding histidine decarboxylase, the rate-limiting enzyme in histamine synthesis. In vivo, treatment with antihistamines pyrilamine or cimetidine decreased lung weight and severity of pneumonia and tracheobronchitis in infected W-sh mice. These findings suggest that neutrophils, provoked by mycoplasma, greatly expand their capacity to synthesize histamine, thereby contributing to lung and airway inflammation.
Abbreviations used: BAL, bronchoalveolar lavage; BMMC, bone marrow–derived mast cell; Ct, cycle threshold; HDC, histidine decarboxylase; HPRT, hypoxanthine guanine phosphoribosyl transferase; PMN, polymorphonuclear neutrophils; W-sh, KitW-sh/KitW-sh.
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