The human gut harbors a wide range of microorganisms that play a fundamental role in the well-being of their host. A dysregulation of the microbial composition can lead to the development or exacerbation of gastrointestinal (GI) disorders. Emerging evidence supports the hypothesis that mast cells (MCs) play a role in host-microbiota communication, modulating the mutual influence between the host and its microbiota through changes in their activation state. The ability of some bacteria to specifically affect MC functions and activation has been extensively studied, with different and sometimes conflicting results, while only little is known about MC-fungi interactions. In this review, the most recent advances in the field of MC-bacteria and MC-fungi interactions will be discussed, with a particular focus on the role of these interactions in the onset of GI disorders such as inflammatory bowel diseases (IBD). Moreover, the connection between some MC-targeting drugs and IBD was discussed, suggesting probiotics as reasonable and promising therapy in the management of IBD patients. Keywords: Inflammatory bowel disease (IBD) r Intestine r Mast cells r Microbiota r Neurons Additional supporting information may be found online in the Supporting Information section at the end of the article. of the high affinity receptor for IgE on the surface of the cell and of the proteases-containing granules in the cytosol, under the influence of tissue-specific molecules (including SCF, IL-3, and IL-9) and bacterial-derived molecules (LPS and peptidoglycan) present in the local microenvironment [1]. Intestinal homing of MCs progenitors is mainly mediated by the interaction of α4β7 integrin expressed by MCs with ICAM-1, V-CAM, or MAdCAM-1 expressed by endothelial cells and it is influenced by CXCR2 ligation [2, 3].MCs possess a great number of costimulatory molecules, including members of the B7 family (ICOSL, PD-L1, and PD-L2,) and of the TNF/TNFR families (OX40L, CD153, Fas, 4-1BB, and glucocorticoid-induced TNFR), which allow them to interact with different partners both from immune and nonimmune cells populations as well as with bacteria and fungi through the expression of different pattern-recognition receptors (PRRs) [4]. Moreover, MCs harbor a high number of cytoplasmic granules that contain preformed immunomodulatory compounds such as proteases, histamine, heparin, and TNF-α. Given the wide pattern Eur.

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The receptor tyrosine kinase cKit and its ligand stem cell factor are essential for mast cells (MC) development and survival. Strains with mutations affecting the Kit gene display a profound MC deficiency in all tissues and have been extensively used to investigate the role of MC in both physiologic and pathologic conditions. However, these mice present a variety of abnormalities in other immune cell populations that can affect the interpretation of MC‐related responses. C57BL/6 KitW‐sh are characterized by an aberrant extramedullary myelopoiesis and systemic neutrophilia. MC deficiency in KitW‐sh mice can be selectively repaired by engraftment with in vitro‐differentiated MC to validate MC‐specific functions. Nevertheless, the impact of MC reconstitution on other immune populations has never been evaluated in detail. Here, we specifically investigated the neutrophil compartment in primary and secondary lymphoid organs of C57BL/6 KitW‐sh mice before and after MC reconstitution. We found that, albeit not apparently affecting neutrophils phenotype or maturation, MC reconstitution of KitW‐sh mice restored the number of neutrophils at a level similar to that of wild‐type C57BL/6 mice. In vitro and ex vivo experiments indicated that MC can influence neutrophil clearance by increasing macrophages’ phagocytic activity. Furthermore, the G‐CSF/IL‐17 axis was also influenced by the presence or absence of MC in KitW‐sh mice. These data suggest that MC play a role in the control of neutrophil homeostasis and that this aspect should be taken into account in the interpretation of results obtained using KitW‐sh mice.

Mast cells (MCs) are tissue-resident, long lived innate immune cells with important effector and immunomodulatory functions. They are equipped with an eclectic variety of receptors that enable them to sense multiple stimuli and to generate specific responses according on the type, strength and duration of the stimulation. Several studies demonstrated that myeloid cells can retain immunological memory of their encounters – a process termed ‘trained immunity’ or ‘innate immune memory’. As MCs are among the one of first cells to come into contact with the external environment, it is possible that such mechanisms of innate immune memory might help shaping their phenotype and effector functions; however, studies on this aspect of MC biology are still scarce. In this manuscript, we investigated the ability of MCs primed with different stimuli to respond to a second stimulation with the same or different ligands, and determined the molecular and epigenetic drivers of these responses. Our results showed that, while the stimulation with IgE and β-glucan failed to induce either tolerant or trained phenotypes, LPS conditioning was able to induce a profound and long-lasting remodeling of the signaling pathways involved in the response against LPS or fungal pathogens. On one side, LPS induced a strong state of unresponsiveness to secondary LPS stimulation due to the impairment of the PI3K-AKT signaling pathway, which resulted in the reduced activation of NF-κB and the decreased release of TNF-α and IL-6, compared to naïve MCs. On the other side, LPS primed MCs showed an increased release of TNF-α upon fungal infection with live Candida albicans, thus suggesting a dual role of LPS in inducing both tolerance and training phenotypes depending on the secondary challenge. Interestingly, the inhibition of HDAC during LPS stimulation partially restored the response of LPS-primed MCs to a secondary challenge with LPS, but failed to revert the increased cytokine production of these cells in response to C. albicans. These data indicate that MCs, as other innate immune cells, can develop innate immune memory, and that different stimulatory environments can shape and direct MC specific responses towards the dampening or the propagation of the local inflammatory response.

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