Recognition of crystalline structures by the immune system

• Applicant: Dr. Konstantin Neumann
• Subject Area: Immunology ; Public Health, Healthcare Research, Social and Occupational Medicine ; Rheumatology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 371496824

The immune system harbours specific receptors that recognize microbes or sterile cell death and induce inflammation upon activation. Among other things, necrotic cells release uric acid, which activates the immune system upon crystallization. Uric acid crystals are also the causative agent of gout, where they cause inflammation in the joints. The crystallization of many other substances is involved in the development of disease, such as calcium oxalate (nephrolithiasis), calcium pyrophosphate (pseudogout) and cholesterol (arteriosclerosis). Proteins can also form crystal-like (amyloid) structures, such as the amyloid beta-peptide, which forms the plaques in the brain of patients with Alzheimer's disease. Inhaled crystalline structures can cause pulmonary diseases such as silicosis or asbestosis.Crystals induce inflammation by several means. Common to all of the above crystals is that they activate intracellular inflammasomes in myeloid cells. Blocking of the products of the inflammasomes has shown promising results in disease models of crystallopathies. It is unclear, however, how myeloid cells recognize the extracellular crystals and transmit the signals via the plasma membrane into the cells.We have investigated the signalling pathways of myeloid immune receptors and showed that Syk-coupled C-type lectin receptors induce inflammatory gene expression via the kinase PKCdelta. We have also studied endogenous receptors that counteract this pathway. For the inhibitory C-type lectin receptor Clec12A we surprisingly found that it recognizes uric acid crystals, and that it inhibits the Syk-dependent immune cell activation by these crystals.In the current project we want to characterize activating crystal recognition receptors and their signalling pathways that lead to inflammation.1. First, we will test whether there are other C-type lectin receptors similar to Clec12A that recognize crystals. We will also investigate unrelated immune receptors for which a participation in the activation by certain crystals has already been shown. We will test whether they themselves bind crystals, transduce signals or are involved in other essential processes.2. Next, we will examine the signal transduction into the cell. We will purify proteins that are phosphorylated in immune cells after activation by crystals and identify them by mass spectrometry. The identified proteins are individually inactivated in human immune cells to characterize their role in immune cell activation by crystals.3. Finally, we will investigate the role of the identified proteins and receptors in preclinical models of crystal-induced inflammatory diseases.The findings of the planned experiments may show whether sterile crystalline structures, similar to microbial structures, are recognised by specific immune receptors and may reveal therapeutic targets for treating inflammatory responses in crystallopathies.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Korbinian Brand