Immune complex-directed cell migration: mechanisms and relevance

• Applicant: Professor Dr. Knut Schäkel
• Subject Area: Dermatology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468026440

Immunoglobulin G (IgG) is important for the antimicrobial immune defense, can cause autoimmune diseases and is successfully used for therapeutic purposes. Understanding of the IgG-mediated immune defense is of great medical and scientific interest. We study the novel role of IgG immune complexes (ICs) in inducing and orienting the migration of non-classical monocytes. We published on the IC-induced local vascular recruitment of human slan+ nonclassical monocytes (slanMo) from blood circulation via low affinity FcγRIII ligation, and demonstrated that these cells serve as the dominant pro-inflammatory cell type in early IC-induced lupus nephritis. Our current studies demonstrate the induction of migration of slanMo by ICs and that gradients of ICs induce a strong directional and oriented migration equivalent to cell migration induced by chemokines. We propose a three-step model of IC-directed cell migration, starting with IC-induced nonclassical monocyte recruitment from blood to the vascular lining, the induction of crawling along the endothelium, turning into an oriented migration when sensing slopes of ICs ramping up in tissues. Thereby, in the absence of chemokines and complement, ICs alone appear to recruit and direct a first wave of immune cells that may prove essential for controlling early microbial infection in a seropositive host or for initiating IgG-dependent autoimmune inflammation. With our studies we will address the following: 1) the molecular and functional mechanisms of IC-induced cell migration, 2) the cells and their specific requirements to allow for IC-induced migration, and 3) the in vivo relevance of these findings. We will address these objectives by transcriptomic studies of migrating cells, by using nano-structured surfaces to be used as migration matrices and by studying proteolytic mechanisms during ligand disengagement. Furthermore, for translational studies we will investigate IC-induced skin inflammation in bone marrow chimeric mice.These studies explore the functional role of IgG-ICs in cell recruitment and add to our understanding of IgG in immune defense. Results of our studies will provide knowledge with the potential for developing treatment strategies aiming at inhibiting IC-driven autoimmune diseases, stimulating pathogen-specific or cancer-directed immune responses.

• DFG Programme: Research Grants