Novel role for CD163 in ozone induced alterations of pulmonary immunity Grant uri icon

abstract

  • Ozone (O3) causes lung injury, exacerbates chronic pulmonary diseases, and critically increases susceptibility to respiratory infections. Epidemiological studies strongly associate air pollution exposures and incidence of respiratory infections, which is important since more than 1/3 of the United States population lives in areas exceeding the current regulatory standards for O3. Though O3 exposure clearly impairs pulmonary host defense, the specific molecular mechanisms of enhanced respiratory pathogen susceptibility remain poorly understood. The definition of such mechanisms requires linking molecular pathways modified by environmental pollutants that are critical to host-pathogen interactions. The scavenger receptor families are one such molecular pathway with. In this proposal, we plan to study the role of the scavenger receptor CD163 in O3-induced alterations of pulmonary immunity. CD163 is a class B scavenger receptor, expressed on monocytes and macrophages, which exists in both membrane-bound and soluble (sCD163) forms. Membrane CD163 clears cell-free hemoglobin (CFH) by recognizing and internalizing hemoglobin-haptoglobin complexes. Once recognized by CD163, the complex is degraded by heme-oxygenase-1 (HO-1) into anti-inflammatory byproducts. Delayed CFH clearance augments inflammatory responses, exacerbates lung diseases, and modifies macrophage phagocytosis and apoptotic cell clearance (efferocytosis) resulting in persistent inflammation and defective pathogen clearance. Thus, defining the role of CD163 in O3-mediated macrophage functions would uncover a novel mechanism mediating O3-induced adverse health effects. Our preliminary studies indicate that CD163 expression is upregulated on bronchoalveolar lavage (BAL) macrophages in human subjects undergoing acute laboratory O3 exposure when compared to expression after filtered air exposure. We also identified an increase in CD163 expression in lung macrophages and BAL CFH in mice exposed to O3. Additionally, CD163 deficient mice exposed to O3 had increased lung injury, neutrophilia and apoptotic neutrophils in the airspace compared to wildtype (WT) controls. Therefore, we hypothesize that macrophage dependent clearance of CFH is mediated by CD163, which limits acute lung injury after O3 to maintain effective efferocytosis, and pathogen phagocytosis. The studies proposed will define: 1) how CD163 limits pulmonary inflammation by promoting efferocytosis; and 2) how CD163 clearance of CFH maintains macrophage phagocytosis of pathogens. These studies will integrate murine and human samples to provide direct translation of the observations. Completion of these studies would define in CFH and CD163 a molecular pathway of O3-induced health effects and define a novel mechanism of how ambient pollutants mediate critical macrophage functions. Furthermore, studies with sCD163 could identify a therapeutic to mitigate O3-induced susceptibility to pulmonary infections.

date/time interval

  • August 2018 - March 2020

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