Transregional Collaborative Research Center SFB-TR 84 - “Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia“

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A1-Subproject

Rezeptoren der angeborenen Immunität in der Kontrolle von Hyperinflammation und Gewebereparatur (Bauer / Opitz)

 

The innate immune response to pathogens in the lung is initiated after detection of microbial molecules (microbe-associated molecular patterns, MAMPs) by pattern recognition receptors (PRRs) including the Toll-like receptors (TLRs), NOD-like receptors and cytosolic DNA sensors. This immune response is vital for preserving lung function (ongoing gas exchange) during pneumonia as it fights the invading microbes. An unrestricted PRR-mediated inflammation as well as an inadequate repair, however, can also lead to extensive tissue damage and the development of acute lung injury/acute respiratory distress syndrome.
Own work performed during the first funding period demonstrated that nucleic acid sensing and type I interferon production differentially regulate the outcome of lung infection. In more detail, we showed that Legionella pneumophila (intracellular, Gram-negative) and Streptococcus pneumoniae (extracellular, Gram-positive) are both recognized by a cytosolic STING-dependent DNA sensing pathway in macrophages that activates a type I IFN response. A direct role for ADAR1 (adenosine deaminase acting on double-stranded RNA) in cytoplasmic nucleic acid sensing was not observed, however ADAR1 differentially regulates IFN-β and IFN-α production in macrophages upon cellular stimulation. In lung infections with L. pneumophila type I IFNs are beneficial for the host. Type I IFNs produced by Legionella-infected macrophages activate a cell-autonomous resistance mechanism that together with type II IFN controls the infection in the lung. Type I IFNs produced by alveolar macrophages in response to S. pneumoniae regulate gene expression in neighboring alveolar epithelial cells and production of RANTES. This type I IFN response, however, is overall detrimental for the host during pneumococcal pneumonia.
Most aspects of nucleic acid sensing during pneumonia have now been addressed, whereas resolution and repair mechanisms of the innate immunity are under-investigated and poorly understood. In the sub-acute phases of pneumonia, the immune response as well as the pathogen itself might trigger a release of endogenous molecules with immune-regulatory functions that are normally hidden inside the cells and only liberated after cell death. Those molecules are called damage-associated molecular patterns (DAMPs) and constitute interesting candidates for molecules that actively regulate resolution and repair. In addition MAMPs derived from the microbiota might be involved in epithelial homeostasis and will be investigated in this context.
Based on those considerations and on interesting preliminary data, we will focus on the function of two molecules of the TLR/interleukin-1 receptor / (TIR) family during the second funding period. ST2 and TIR8 (SIGIRR) have been implicated in the negative control of PRR-mediated inflammatory responses and/or promotion of repair processes. ST2 serves as a receptor for the DAMP IL-33 and is involved in recruiting type 2 innate lymphoid cells (ILC2) that in turn might regulate healing processes in the lung. We will test the following hypotheses: (I) ST2 negatively regulates innate immune responses in the sub-acute phase of bacterial pneumonia after detection of the DAMP IL-33. (II) IL-33 is released during bacterial pneumonia and recruits ST2-expressing ILC2s that mediate repair at a later phase of pneumonia. (III) The immune-regulatory function of TIR8 during pneumonia depends on recognition of MAMPs or DAMPs and caspase-1 regulates the TIR8 transport