Histamine Plays an Essential Regulatory Role in Lung Inflammation and Protective Immunity in the Acute Phase of Mycobacterium tuberculosis Infection
2009
Carlos, D. | Fremond, C. | Samarina, A. | Vasseur, V. | Maillet, I. | Ramos, S.G. | Erard, F. | Quesniaux, V. | Ohtsu, H. | Silva, C.L. | Faccioli, L.H. | Ryffel, B.
The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC⁻/⁻), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC⁻/⁻ mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC⁻/⁻ mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), in the acute phase of infection. However, the accumulation and activation of CD4⁺ T cells were augmented in the lungs of infected HDC⁻/⁻ mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c⁺ cell influx into the lungs of infected HDC⁻/⁻ mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-α but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.
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