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Please note this is a comparison between Version 1 by Paulina Żelechowska and Version 2 by Jessie Wu.
Mast cells take part in host defense against various microorganisms as they are numerous at the portal of infection, exert several essential mechanisms of pathogen destruction, and they express pattern recognition receptors. MCs can support immune responses to fungi and their specific constituents through initiated degranulation, synthesis and release of cytokines, chemokines, mediators, and generation of reactive oxygen species (ROS), as well as immune cells' recruitment, phagocytosis, or formation of extracellular DNA traps.
- mast cell
- fungi
1. Background
The prevalence of fungal infections presents a global health issue and has been escalating in recent years. Due to the common multidrug resistance as well as lack of effective antifungal remedies, fungal infections have become increasingly difficult to treat. Moreover, in contrast to bacterial or viral infections, a successful vaccine against pathogenic fungi has not yet been developed [1][2][1,2]. Since fungi are ubiquitous in the environment, we are constantly and directly exposed to them on many levels. Furthermore, fungi form an integral part of the microbiome, which plays a role as a reservoir for opportunistic pathogens. The mycobiome maintains body homeostasis and influences the immunological responsiveness in the host organism. However, it has been reported that altered immune system function or mycobiome composition play an important role in several human diseases [3]. Despite the close encounters with fungi, the host defense mechanisms against various fungal pathogens are not fully known. One of the significant challenges is the unique structure of the fungi cell wall, which is the crucial element involved in the interaction with the host. In general, the fungal cell wall is a rigid structure composed of various types of linear and branched polysaccharides, glycoproteins, proteins, lipids, and other components. These components may be organized into at least two layers (Figure 1). The inner layer of most pathogenic fungi consists of a core of glycans, including chitin, which is located closest to the plasma membrane, and β-1,3- and β-1,6-glucans adjacent to the chitin fibers. It has been indicated that 50–60% of the dry weight of this structure is made up of glucan with β-1,3-glycosidic linkages. Many fungi have an inner cell wall layer that also contains complex polymerized and/or indolic compounds called melanins. On the other hand, the composition of the outer layer may vary among fungal species, but generally, it is composed of α-1,3-glucans or homopolymers of mannose, such as mannans and mannoproteins [4].
Figure 1. Structural organization and composition of the fungal cell wall.
Host defense against various pathogens, primarily bacteria and viruses, involves the orchestration of first-line innate immune responses and adaptive immunity mechanisms. The course of these processes depends to a large extent on the involvement of mast cells (MCs). However, no sufficient data have been found on MCs’ contribution to defense against fungi. This review summarizes current knowledge of host defense mechanisms against fungi and MCs’ involvement in those processes. It also provides insight into the effects of fungi or specific fungus-derived constituents on MCs’ activity.
2. How Do MCs Contribute to the Host Defense?
MCs play a pivotal role in the host defense against pathogenic microorganisms for several reasons. First of all, MCs’ strategic position at the host–external environment interfaces, i.e., in the subepithelial layers of the skin, the respiratory system, or in the gastrointestinal and genitourinary tracts, means that they are among the first cell population to interact with invading microbes along with other innate immune cells, such as epithelial cells, and trigger a response against them. Moreover, it is well known that MCs may initiate and combat the clearance of pathogens by several mechanisms of action [5][6][7][18,19,20]. MCs possess an array of bioactive substances, which affect all stages of inflammation during infection, including its initiation, maintenance, and even resolution. They include granule-associated preformed mediators (e.g., histamine, tryptase, chymase, carboxypeptidases, metalloproteinases, proteoglycans), de novo-produced eicosanoid metabolites (e.g., leukotrienes (LTs), prostaglandins, thromboxanes), as well as many newly synthesized cytokines/chemokines [8][9][10][11][12][21,22,23,24,25]. MC activity against pathogens also involves the release of some antimicrobial peptides and the production of ROS. Moreover, these cells can engulf invading microbes via phagocytosis and kill them through oxidative and non-oxidative systems [5][6][18,19]. Another described strategy used by MCs to destroy microorganisms is through extracellular traps (MCETs) composed of DNA, histones, and granule proteins [13][26]. The relevance of MCETs has been documented in antibacterial, antifungal, or antiparasitic host defense [14][15][27,28]. Following phagocytosis, MCs may process pathogen antigens for presentation through class I and II MHC molecules, which leads to the development of adaptive antimicrobial immunity [16][29]. As MCs express PRRs, they may act as effectors of host defense through their ability to detect various MAMPs or endogenous DAMPs released in response to infection. The available data indicate that among PRRs expressed on MCs, there are representatives from TLRs, RLRs, and NLRs, as well as CLRs [17][30]. It has been reported that MCs can recognize bacterium-associated molecules, such as lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN) mainly through TLRs but also via some NLRs. In turn, specific TLRs and RLRs are involved in MC response to viral dsRNA, ssRNA, or envelope proteins. Among PRRs expressed on MCs, there are also molecules from the CLR group or some TLRs, which may sense different fungal components (Figure 2) [17][30]. However, little information exists concerning MC involvement in antifungal host defense, and the function of MCs in fungal infections is not precisely defined [18][19][31,32].
Figure 2. Expression of PRRs involved in sensing different fungal components on MCs.
3. Expression of PRRs Involved in Fungus Recognition in MCs
It is well known that CLR family members are strongly involved in recognizing fungi and their components [20][33]. However, data showing the expression of these receptors within MCs are still limited. Among investigated receptors from the CLR group, the most presented reports concerned Dectin-1 primarily. Only a handful of studies revealed the expression of Dectin-2, MR, or Mincle within MCs, whereas Dectin-3’s presence on these cells has not been investigated yet. The constitutive expression of Dectin-1 has been confirmed in bone marrow-derived MCs (BMMCs) [21][34], cord blood-derived MCs (CBMCs) [22][35], a human leukemic cell line (KU-812) that displays enhanced tryptase expression [22][35], the rat basophilic leukemia clone 2H3 cell line (RBL-2H3), i.e., mucosal-like MCs [23][36], and tryptase-positive progenitor-derived MCs [24][37], both at mRNA and protein levels. We have recently documented that rat connective tissue type MCs, i.e., peritoneal MCs (PMCs), also constitutively express Dectin-1 and Dectin-2 mRNA and protein [25][26][38,39]. To date, the expression of mRNA and protein of Mincle has been demonstrated only in RBL-2H3 cells [27][40] and tryptase-positive progenitor-derived MCs [24][37]. The protein expression of MR was documented in murine BMMCs and PMCs [28][41].
Expression of all known members from the TLR family has been confirmed in a wide range of MC types and cell lines. However, as mentioned earlier, it has been established that only certain TLRs participate in fungus sensing. Among them, the most important for fungus detection seems to be TLR4. The mRNA or protein expression of TLR4 was documented in a mouse MC line (MC/9) [29][42], in MC lines that closely resemble primary human MCs, i.e., a human MC line (HMC-1) and Laboratory of Allergic Diseases 2 (LAD2) cells [30][43], murine BMMCs [31][44], murine fetal skin-derived cultured MCs (FSMCs) that exhibit important features of connective tissue type MCs [31][44], and CBMCs [32][45], as well as rat and murine PMCs [31][33][44,46]. TLR2 is another well-characterized PRR participating in fungus recognition. Available data indicate that mRNA and/or protein expression of TLR2 are found in MC/9 [29][42], HMC-1 and LAD2 cells [30][34][43,47], murine BMMCs and FSMCs [31][35][44,48], CBMCs [32][45], and in mature rat PMCs [33][46]. Since TLR2 forms heterodimers with TLR6 to recognize fungal components, it should be stressed that its expression has also been documented on different MC types, including MC/9 [29][42], HMC-1, LAD2 cells [36][49], human cultured MCs (HCMCs) [36][49], FSMCs and BMMCs [31][44], CBMCs [32][45], and rat PMCs [33][46].
An interesting observation is that fungi or fungus-derived constituents may modulate the expression of some PRRs in MCs. Ribbing et al. [24][37] documented that the stimulation of tryptase-positive progenitor-derived MCs with Malasezzia sympodialis extract or after IgE receptor cross-linking resulted in an increased expression of Mincle mRNA. Saccharomyces cerevisiae-derived zymosan, i.e., β-1,3-glucan containing mannan particles, significantly upregulates surface expression of the Dectin-1 receptor in murine BMMCs [21][34]. Only a few reports exist regarding the effect of various endogenous factors on PRRs involved in fungus recognition in MCs. Our observations provided evidence that IL-6 treatment of PMCs induces an increase in TLR4 expression, whereas exposure of those cells to CCL5 results in decreased expression of both TLR2 and TLR4 [37][50]. Okumura et al. [38][51] found that IFN-γ upregulates TLR4 expression on human peripheral blood-derived MCs and Yang et al. [39][52] demonstrated that IL-12 induces a significant increase in the expression of TLR2 and TLR4 mRNAs and proteins in the P815 cell line. Our recent data have revealed that one of the well-known antimicrobial peptides, i.e., cathelicidin LL-37, increases TLR2 and TLR4 expression in the PMCs [40][53]. Similar observations were made by Yoshioka and colleagues [41][54] as they observed augmented TLR4 expression in LAD2 cells in response to LL-37.