Immunity and Asthma
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Immunity and Asthma |
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In collaboration with the
laboratories of Randall
Johnson
in the UCSD Division of Biology and Emmanuel Theodorakis
in the UCSD
Department of Chemistry and Biochemistry, we are examining the role of
transcription factor HIF-1α as a key regulator of the bactericidal and
inflammatory capacity of macrophages and neutrophils. We are also
examining the role of HIF-1α in modulating airway inflammation and
reactivity in asthma.
Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. We have used the conditional gene targeting reagents developed in the Johnson laboratory to examine the contribution of hypoxia-responsive transcription factor HIF-1α to myeloid cell innate immune function. HIF-1α isinduced by bacterial infection, even under normoxia, and regulates the production of key immune effector molecules including granule proteases, antimicrobial peptides, nitric oxide and TNF-α. Mice lacking HIF-1α in their myeloid cell lineage show decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1α pathway through vHL deletion or pharmacologic inducers supports myeloid cell production of defense factors and improved bactericidal capacity.  The placement of essential
microbial killing functions of white blood cells under regulation of
HIF-1 represents an elegant controlled response system. The white
blood cells are in a resting state as they circulate in the oxygen-rich
bloodstream, but can then be activated in response to the declining
oxygen gradient encountered upon migration to sites of infection.
Direct encounter with the bacteria then activates the neutrophils and
macrophages maximally. Under HIF-1 regulation, antimicrobial genes are
expressed only in infected tissues and not in healthy tissues where
they could produce unwanted inflammatory damage.
 These findings suggest a potential novel approach to treatment of difficult infections such as those produced by antibiotic resistant bacteria or those affecting patients with weakened immune systems due to chronic disease, cancer chemotherapy or AIDS. Rather than designing drugs to target the bacteria, medications that promote HIF-1 activity could be used to boost the bacterial killing ability of white blood cells and promote the resolution of infection through the actions of our natural immune defenses. Conversely, strategies to reduce HIF-1 activation could be of therapeutic benefit in mitigating the chronic inflammation of asthma. |
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