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Mycobacterium tuberculosis bio-lipid mycolic acid and mammalian cholesterol-sensor liver X receptor in airway immunity
Book - Dissertation
Within this dissertation we have first addressed macrophage (MΦ) and airway responses in mice to the complex Mycobacterium tuberculosis bio-lipid mycolic acid (MA) with respect to its chemical fine-structure. This revealed a distinct inflammatory capacity, and even anti-inflammatory effects, dependent on the MA cyclopropane stereochemistry and oxygenation type. These chemical moieties on MAs also impacted on the induction of foam cells due to MΦ intracellular cholesterol accumulation. Also, the MA chemistry was found to be important for the previously described T-helper 2 cell (Th2)-tolerizing anti-inflammatory effect in the airways of asthma model mice, coinciding with shifts in Th-cell lineages balances. Additionally, we have identified possible novel molecular interactions between MA and host cell signaling protein molecules that could in part explain the observed biological functions. Thus, MAs could selectively precipitate the 65kDA regulatory subunit of protein phosphatase A from mouse MΦ cytosolic protein lysates and they could furthermore suppress the ligand-mediated activation of gene-transcription by retinoid X receptor-permissive nuclear receptors, liver X receptor (LXR) and retinoic acid receptor. All three of these mammalian proteins are involved in cellular lipid household and lipid signaling events, but also exert some level of control on inflammation and immunity. Second, the importance of LXR subtypes α and β for protection against pulmonary M. tuberculosis infection was studied and we found that functional LXR-α in particular was required for full-blown neutrophil and Th17-mediated anti-tuberculous immunity. Further dissection of this observed immune control by LXR was performed based on the application of an in-house established non-infectious Th1/Th17-driven airway allergic inflammatory model for neutrophilic severe refractory asthma. This revealed that LXR-α knock-out (KO) and LXR-α,β double KO mice, but not LXR-β KO or wild-type mice, indeed mirrored the Th17 immune defect observed in the infectious model. This was further ascribed to the lack of LXR endogenous functions at the time of allergic inflammation in response to airway allergen exposure, rather than to Th-cell intrinsic effects. In contrast, by the use of an analogous mouse model for mild eosinophilic asthma, we observed that the Th2-mediated eosinophil inflammatory response was reduced by LXR-deficiency. Preliminary data identify possible functional involvement of LXRs in processes driving eosinophil chemotaxis to the site of inflammation and Th2-cel cytokine-induced de novo eosinopoiesis by bone marrow progenitor cells in response to repeated airway allergen exposure. In conclusion, the data presented here are indicative for an active utilization of the host lipid signaling pathways by mycobacterial MAs to manipulate the host cellular response to infection. This level of control could further be fine-tuned by the relative abundance of certain types of MA chemical modifications and that were here associated with distinct potencies of MAs to exert biological functions in inflammation and cholesterol homeostasis. Additionally, we have shown that the mammalian cholesterol homeostasis regulator LXR is indispensible for effective anti-tuberculous Th17-dependent immunity and furthermore contributes to allergen-induced Th2-effector eosinophil responsivity in the airways.
Number of pages: 1