Mast cell responses to danger signals

Sammanfattning: Detecting and responding to danger is a paramount function of the immune system. Compounds heralding danger can be divided into two groups: exogenous and endogenous danger signals. The former group consists of conserved microbial structures such as lipopolysaccharide (LPS), while the latter consists of host compounds released or exposed by dead or dying cells as a consequence of trauma, stress or infection. Mast cells are long-lived immune cells present in almost all tissues, and are especially numerous at sites facing the external environment, making them ideal responders to danger signals. The aim of the work presented in this thesis was to investigate mast cell responses to danger signals of exogenous and endogenous origin. In Paper I, we investigated mast cell responses to the exogenous danger signal M-TriDAP, a bacterial peptidoglycan degradation product. We found that cord bloodderived mast cells (CBMCs) express NOD1, the receptor for M-TriDAP. Furthermore, M-TriDAP-treatment of CBMCs resulted in degranulation-independent release of cytokines and chemokines such as TNF, IL-8/CXCL8, MIP-1α/CCL3 and MIP-1β/CCL4. Importantly, we observed an augmented response when M-TriDAP was combined with the TLR4 agonist LPS, indicating cooperation between intracellular and extracellular pattern recognition receptors. In Paper II, we investigated mast cell responses to cell injury by subjecting murine mast cells to the supernatant of fibroblasts rendered necrotic by freeze-thawing. We found that mast cells respond to cell injury in this model by initiating a proinflammatory response, characterized by degranulation-independent release of cytokines and leukotrienes. By using genetically modified mice and molecular inhibitors, we found that the recognition of cell injury was MyD88-, T1/ST2- and p38- dependent. Finally, by using RNA-interference, we could pinpoint IL-33 as the necrotic cell compound that was responsible for the mast cell activation. In Paper III, we investigated responses to IL-33 administration in vivo. Here we found that wild-type C57BL/6 mice respond to intraperitoneal IL-33 administration with neutrophil infiltration. This response was not observed in mast cell-deficient mice but could be restored upon mast cell reconstitution, thus demonstrating a mast cell dependent mechanism. In Paper IV, we investigated the hypothesis that mast cells might function as sensors of damaged epithelia by responding to IL-33 during chronic inflammations of the airways, for instance in asthma. We found that IL-33 is released from necrotic airway epithelial cells and that CBMCs respond to the necrotic supernatant of these cells by secreting IL-5, IL-8/CXCL8, TNF and GM-CSF. However, no release of histamine, LTB4 or PGD2 could be detected. Interestingly, the exact same mediator release pattern was observed when CBMCs were treated with recombinant IL-33, suggesting that IL-33 might be an important factor released by injured airway epithelial cells that activates mast cells. In conclusion, the work presented in this thesis provides further evidence for important roles of mast cells in innate immune responses. The function of mast cells as sensors of cell injury is highlighted; a role that potentially can be either beneficial or detrimental. Finally, novel evidence is provided for the notion that IL-33 is an important danger signal capable of mast cell activation.

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