Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA sequencing datasets to generate a pan-organ analysis of MCs in mice and humans at steady state. In mice, we identify two mutually exclusive MC populations, MrgprB2+ connective tissue–type MCs and MrgprB2neg mucosal-type MCs, with specific transcriptomic core signatures. While MrgprB2+ MCs develop in utero independently of the bone marrow, MrgprB2neg MCs develop after birth and are renewed by bone marrow progenitors. In humans, we unbiasedly identify six MC clusters/states (MC1–6) distributed across 12 organs with different transcriptomic core signatures. MC1 are preferentially enriched in the skin and lungs, MC2, MC3, and MC4 in the skin and bladder, MC5 in the lymph node and vasculature, and MC6 in the trachea and lungs. This comprehensive analysis offers valuable insights into the natural diversity of MC subtypes in both mice and humans.

Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non‐immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells, and epithelial cells. During recent years, clinical and experimental studies on human mast cells, as well as experiments using animal models, have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review, we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity, and reactivity. We also highlight the development in our understanding of mast cell‐driven diseases and discuss the development of novel strategies to treat such conditions.

Mast cells are now recognized as key players in diverse pathologies, but the mechanisms by which they contribute in such settings are only partially understood. Mast cells are packed with secretory granules, and when they undergo degranulation in response to activation the contents of the granules are expelled to the extracellular milieu. Chymases, neutral serine proteases, are the major constituents of the mast cell granules and are hence released in large amounts upon mast cell activation. Following their release, chymases can cleave one or several of a myriad of potential substrates, and the cleavage of many of these could potentially have a profound impact on the respective pathology. Indeed, chymases have recently been implicated in several pathological contexts, in particular through studies using chymase inhibitors and by the use of chymase-deficient animals. In many cases, chymase has been shown to account for mast cell-dependent detrimental effects in the respective conditions and is therefore emerging as a promising drug target. On the other hand, chymase has been shown to have protective roles in other pathological settings. More unexpectedly, chymase has also been shown to control certain homeostatic processes. Here, these findings are reviewed.

It is now well established that mast cells (MCs) play a crucial role in asthma. This is supported by multiple lines of evidence, including both clinical studies and studies on MC-deficient mice. However, there is still only limited knowledge of the exact effector mechanism(s) by which MCs influence asthma pathology. MCs contain large amounts of secretory granules, which are filled with a variety of bioactive compounds including histamine, cytokines, lysosomal hydrolases, serglycin proteoglycans and a number of MC-restricted proteases. When MCs are activated,e.g.in response to IgE receptor cross-linking, the contents of their granules are released to the exterior and can cause a massive inflammatory reaction. The MC-restricted proteases include tryptases, chymases and carboxypeptidase A3, and these are expressed and stored at remarkably high levels. There is now emerging evidence supporting a prominent role of these enzymes in the pathology of asthma. Interestingly, however, the role of the MC-restricted proteases is multifaceted, encompassing both protective and detrimental activities. Here, the current knowledge of how the MC-restricted proteases impact on asthma is reviewed.