Periodic Reporting for period 4 - IMMUNE CELL SWARMS (Innate Immune Cell Swarms: Integrating and Adapting Single Cell and Population Dynamics in Inflamed and Infected Tissues)
Période du rapport: 2021-08-01 au 2022-01-31
In this project we investigated the mechanisms that stop neutrophil swarming in mammalian tissues. The stop signals may be derived from cells of the surrounding inflammatory environment or from neutrophils themselves. We hypothesized that the attractants released by neutrophils may become highly concentrated at sites where these cells cluster in larger numbers. It is well established that high chemoattractant concentrations can attenuate cellular responses by a process termed GPCR desensitization. We hypothesized a self-limiting mechanism for swarming: The local accumulation of the same neutrophil-expressed attractants that amplify swarming during early stages would cause desensitization of their respective GPCRs at later stages of neutrophil clustering. This led us to investigate the role of GPCR desensitization in neutrophil tissue navigation and host defense.
Our results describe a cell-intrinsic stop mechanism for the self-organization of neutrophil collectives in infected tissues, which is based on sensing the local accumulation of the same cell-secreted attractants that amplify swarming during early stages. GPCR desensitization acts as a negative feedback control mechanism to stop neutrophil migration in swarm aggregates. A protein called G-protein receptor coupled kinase 2 (GRK2) critically controls GPCR desensitization during neutrophil swarming. This navigation mechanism allows neutrophils to self-limit their dynamics within forming swarms and ensures optimal elimination of bacteria. However, this response is not a general mechanism used by all immune cells, as we find other roles of GRK proteins in other immune cell subsets.
Moreover, we also explored the functional role of GRK-controlled GPCR desensitization in immune cells other than neutrophils. We considered this process as a general mechanism that might influence the dynamics of other immune cells in a similar manner to neutrophils. However, we made the unexpected finding that GRK-deficient dendritic cells, T cells and B cells have completely different phenotypes than GRK-deficient neutrophils, and we further delineated distinct functional roles of GRKs in specific immune cell subsets. A research manuscript is currently prepared for the presentation of these findings. Lastly, in our efforts to develop an integrated view of how different immune cell populations influence neutrophil swarming, we made the unexpected observation that mast cells, a tissue-resident myeloid immune cell type, can influence swarming neutrophils. We could identify the signals that mast cells release to initiate the formation of neutrophil swarms. These unexpected findings shed a new light on the role of neutrophils and mast cells during allergic reactions. A research manuscript is currently prepared for the presentation of these findings.