Lymphatic- and neutrophil-dependent tissue damage in contact hypersensitivity and rheumatoid arthritis
Aradi Petra
Molecular Medicine
Dr. Enyedi Péter
SE Élettani Intézet könyvtára
2024-10-14 13:00:00
Cellular and Molecular Physiology
Dr. Hunyady László
Dr. Jakus Zoltán
Dr. Szolnoky Győző
Dr. Kiss Norbert
Dr. Wiener Zoltán
Dr. Gyöngyösi Norbert
Dr. Uzonyi Barbara
Inflammation is a crucial part of the body’s defense process, by which the immune system recognizes and eliminates the harmful stimuli followed by the healing process. Inflammation involves a coordinated interaction between immune cells, blood and lymphatic vessels, and molecular mediators to restore tissue homeostasis. However, shifts in the inflammatory response from short- to long-lived can disrupt immune tolerance and result in significant changes across all tissues and organs elevating the susceptibility to various non-communicable diseases. Chronic inflammatory conditions, such as diabetes, autoimmune diseases, or allergy represent the most substantial risk to human health according to the World Health Organization.
Our study aimed to better understand the neutrophil- and lymphatic-dependent processes in tissue injury of different inflammatory diseases such as autoimmune rheumatoid arthritis and contact hypersensitivity.
In our study, we were able to investigate the lymphatic vessels separately during the two distinct phases of contact hypersensitivity using various mouse models. Our findings showed reduced inflammation and neutrophil infiltration in mice lacking lymphatics during both sensitization and elicitation phases, with a similar attenuated phenotype with lymphatic deficiency only during sensitization. Conversely, mice deficient in lymphatics only during elicitation exhibited heightened inflammation driven by increased neutrophil infiltration.
Moreover, re-expression of wild-type and ITAM tyrosine mutant (Y65F/Y76F) FcRγ restored activating Fcγ receptor expression in FcRγ-deficient neutrophils. However, only the wild-type transgenic form mediated Fcγ receptor-dependent effector functions, leading to autoimmune arthritis in mice.
In conclusion, skin lymphatics play a crucial but distinct role in CHS's sensitization and elicitation phases. They contribute to immune cell sensitization during the first phase while they can moderate the inflammation and immune cell infiltration during elicitation. Additionally, our findings underscore the critical role of FcRγ ITAM tyrosines in inducing neutrophil effector responses and driving the initiation and progression of autoantibody-induced experimental arthritis in vivo, suggesting a signaling function beyond receptor stabilization.
