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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B5-Subproject

Paralysis of pulmonary immunity after cerebral ischemia by parasympathetic nervous system (Meisel C / Meisel A)

  

Over the last decade, compelling experimental and clinical evidence was provided that acute CNS trauma facilitates the development of pneumonia, the most important medical complication in affected patients, due to temporary inhibition of peripheral immune responses induced by overactivation of neurohumoral stress pathways, a phenomenon termed CNS injury-induced immunodepression syndrome (CIDS).  In the last funding period, we have demonstrated in a clinically relevant experimental mouse model of cerebral ischemia (middle cerebral artery occlusion model) that an increased parasympathetic activity after stroke impairs innate anti-bacterial pulmonary immune responses involving the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on alveolar epithelial cells (AECs) and macrophages (AMs). Blockade of cholinergic anti-inflammatory signalling  by vagotomy or by using mice deficient of the α7nAChR prevented the development of spontaneous bacterial pneumonia after stroke, which was associated with a normalized TLR-ligand induced pro-inflammatory cytokine and chemokine secretion by AECs and AMs.

In the next funding period, we want to characterize the molecular mechanisms by which stroke-induced activation of the anti-inflammatory cholinergic pathway inhibits activation of protective pulmonary anti-bacterial innate immune responses. We will determine the role of other non α7-subunit nicotinic ACh receptors expressed on AECs and AMs for post-stroke lung infections. Furthermore, we will investigate at which molecular level stroke-induced cholinergic anti-inflammatory signalling interferes with activation of TLR pathways in pulmonary myeloid and epithelial cells. Finally, in order to device potential therapeutic measures for prevention of bacterial infections in patients with acute CNS lesions we will investigate in our stroke model the efficacy and safety of different local immunostimulatory treatment regimens to reverse stroke-induced susceptibility to pulmonary bacterial infections.