Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency.

BACKGROUND: Mast cells (MCs) are best known as key effector cells of allergic reactions, but they also play an important role in host defense against pathogens. Despite increasing evidence for a critical effect of MCs on adaptive immunity, the underlying mechanisms are poorly understood. OBJECTIVE: Here we monitored MC intercellular communication with dendritic cells (DCs), MC activation, and degranulation and tracked the fate of exocytosed mast cell granules (MCGs) during skin inflammation. METHODS: Using a strategy to stain intracellular MCGs in vivo, we tracked the MCG fate after skin inflammation-induced MC degranulation. Furthermore, exogenous MCGs were applied to MC-deficient mice by means of intradermal injection. MCG effects on DC functionality and adaptive immune responses in vivo were assessed by combining intravital multiphoton microscopy with flow cytometry and functional assays. RESULTS: We demonstrate that dermal DCs engulf the intact granules exocytosed by MCs on skin inflammation. Subsequently, the engulfed MCGs are actively shuttled to skin-draining lymph nodes and finally degraded inside DCs within the lymphoid tissue. Most importantly, MCG uptake promotes DC maturation and migration to skin-draining lymph nodes, partially through MC-derived TNF, and boosts their T-cell priming efficiency. Surprisingly, exogenous MCGs alone are sufficient to induce a prominent DC activation and T-cell response. CONCLUSION: Our study highlights a unique feature of peripheral MCs to affect lymphoid tissue-borne adaptive immunity over distance by modifying DC functionality through delivery of granule-stored mediators.

Mast Cells Are Critical Regulators of Bone Fracture-Induced Inflammation and Osteoclast Formation and Activity.

Mast cells, important sensor and effector cells of the immune system, may influence bone metabolism as their number is increased in osteoporotic patients. They are also present during bone fracture healing with currently unknown functions. Using a novel c-Kit-independent mouse model of mast cell deficiency, we demonstrated that mast cells did not affect physiological bone turnover. However, they triggered local and systemic inflammation after fracture by inducing release of inflammatory mediators and the recruitment of innate immune cells. In later healing stages, mast cells accumulated and regulated osteoclast activity to remodel the bony fracture callus. Furthermore, they were essential to induce osteoclast formation after ovariectomy. Additional in vitro studies revealed that they promote osteoclastogenesis via granular mediators, mainly histamine. In conclusion, mast cells are redundant in physiologic bone turnover but exert crucial functions after challenging the system, implicating mast cells as a potential target for treating inflammatory bone disorders. © 2017 American Society for Bone and Mineral Research.