Myeloid C‐type lectin receptors in skin/mucoepithelial diseases and tumors

Abstract Myeloid C‐type lectin receptors (CLRs), which consist of an extracellular carbohydrate recognition domain and intracellular signal transducing motif such as the immunoreceptor tyrosine‐based activation motif (ITAM) or immunoreceptor tyrosine‐based inhibitory motif (ITIM), are innate immune receptors primarily expressed on myeloid lineage cells such as dendritic cells (DCs) and Mϕs. CLRs play important roles in host defense against infection by fungi and bacteria by recognizing specific carbohydrate components of these pathogens. However, these immune receptors also make important contributions to immune homeostasis of mucosa and skin in mammals by recognizing components of microbiota, as well as by recognizing self‐components such as alarmins from dead cells and noncanonical non‐carbohydrate ligands. CLR deficiency not only induces hypersensitivity to infection, but also causes dysregulation of muco‐cutaneous immune homeostasis, resulting in the development of allergy, inflammation, autoimmunity, and tumors. In this review, we introduce recent discoveries regarding the roles of myeloid CLRs in the immune system exposed to the environment, and discuss the roles of these lectin receptors in the development of colitis, asthma, psoriasis, atopic dermatitis, and cancer. Although some CLRs are suggested to be involved in the development of these diseases, the function of CLRs and their ligands still largely remain to be elucidated.


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or expressed on tumor cells. 18 Hence, in this review, we will discuss the roles of myeloid CLRs in the development of diseases of the skin and mucoepithelial tissues as well as in the development of tumors.

Colitis
To maintain mucosal homeostasis, the intestinal immune system has to deal with contradictory requirements; the system must be tolerant of commensal microbiota and food components, but fight against SIGN-R3 expressed on myeloid-derived cells binds intestinal fungi by recognizing fungal glycan structures. DECTIN-1 expressed on myeloidderived cells also recognizes food-derived -glucans to induce IL-17F, which stimulates epithelial cells to secret antimicrobial protein S100A8 and phospholipase A2 to inhibit the growth of Lactobacillus murinus and Clostridium cluster XIVa, respectively. Both Lactobacillus and Streptococcus are recognized by MGL1 and induce IL-10 and TGF-, promoting the expansion of Treg cells and also directly suppressing inflammation. Clostridium XIVa also induces Treg differentiation by producing short-chain fatty acids (SCFA). On the other hand, DECTIN-1 expressed on human intestinal epithelium induces the production of IL-8 and CCL2 after -glucan stimulation, which may recruit neutrophils to mediate inflammation Deficiency of CARD9, a downstream adaptor protein of ITAMmediated CLR signaling, also causes intestinal fungal expansion and aggravates colitis; oral inoculation of Lactobacillus murinus can ameliorate this intestinal inflammation. 26 The authors of that study suggested that reduced levels of IL-22, which is important for the recovery from colitis, is responsible for the increased susceptibility to colitis rather than increased fungal growth in Card9 -/mice, and showed that IL-22 is induced by aryl hydrocarbon receptor ligands produced by commensal bacteria including Lactobacillus family members. 26 DECTIN-1 is expressed in freshly isolated human intestinal epithelial cells (IECs) and human IEC lines, but not in the analogous mouse cells. 27 Stimulation of human IECs with -glucans induces IL-8 and CCL2 secretion, which can be blocked by SYK inhibition, 27  binds Streptococcus species and Lactobacillus species to induce IL-10 production in vitro. 29 Mice lacking this molecule develop more severe inflammation after DSS-treatment, accompanied with impaired IL-10 secretion. 29 Although MCL and DCIR also bind some intestinal commensal microbiota, mice deficient in these molecules develop slightly more severe DSS-induced colitis. 30 Another report showed that DCIR-deficient mice develop even milder colitis, with reduced neutrophil-attracting chemokine MIP-2 and decreased accumulation of neutrophils. 31  with an enhanced TNF production. 34 The detailed functional roles of these myeloid CLRs remain to be elucidated.

Asthma and allergic diseases
Asthma, one of most common chronic respiratory diseases, is associated with airway inflammation and remodeling. Possible alterations of asthmatic patient airway structure include mucous gland and goblet cell hyperplasia, modification of epithelial cells, subepithelial fibrosis, constriction of airway smooth muscle, and changes in blood vessels. 35 Numerous cytokines, including IL-9, IL-13, IL-17, IL-22, IL-25, and other inflammatory mediators, are involved in the airway remodeling. 36,37 Despite being classified as a single disease, the term "asthma" subsumes pathologically distinct complex diseases, often accompanied by other morbidities, complicating patient state and decisions about treatment regimen. 38 Frequently, asthma originating in childhood may continue at older ages. To a large extent, asthma developed in children is associated with allergy and atopic disease. Atopic asthma is caused by type 2 immune responses with enhanced IgE production, followed by eosinophilia and mast cell activation. 39 Asthma can also be diagnosed at any age in adulthood. However, the majority of adult-diagnosed asthma is Th2-low and non-atopic, and is often associated with high neutrophil concentrations and elevated Th17related responses. 40,41 Importantly, Th2-high and Th2-low forms of asthma exhibit distinct responses to corticosteroid treatment; Th2high asthmatics respond to this treatment, whereas Th2-low patients are refractory. 38 CLRs are thought to be involved in both forms of asthma (Fig. 2).

Leukotrienes, Prostaglandins
IgE β -g lu c a n s α -m a n n a n s D e r p -1 P r o t e a s e a n t i g e However, its role in allergy-related processes remains to be elucidated.

HDM-associated asthma
HDMs are another widespread cause of AHR response and allergy. 63 HDM allergens include proteases of Dermatophagoides pteronyssinus reported as a receptor for chitin, but its role in asthma remains to be elucidated. 67 Components of HDM extract also trigger cysteinyl leukotriene generation by CD11c + DCs through the activation of the DECTIN-2-SYK pathway, 56 and activates Th2 immune responses. 55

Psoriasis
Psoriasis is a chronic inflammatory skin disease characterized by proliferation, ultimately resulting in hyperplasia of the skin (Fig. 3).
The antimicrobial protein LL37, which is produced by keratinocytes, is thought to activate TLR7 and TLR8 by forming a complex with RNA. 82 Thus, innate immune responses, but not acquired immune responses,  Among these pathogens, the best characterized is Staphylococcus aureus, which is detected in approximately 90% patients and is associated with disease exacerbation. The non-myeloid CTL mannosebinding lectin contributes to defense against this bacterium by activating the complement lectin pathway via an interaction with specific polysaccharide structures. Malassezia, a commensal fungus on the skin, is also thought to cause AD by producing a variety of immunogenic proteins that elicit specific IgE immune responses. 92

CONCLUDING REMARKS
In this review, we described the roles of myeloid CLRs in diseases of muco-epithelial tissues. Recent progress in research on myeloid CLRs has revealed that in addition to the host defense against pathogens, these molecules play important roles in the homeostasis of muco-epithelial immunity and development of diseases, including colitis, asthma, psoriasis, atopic dermatitis, and cancers. The functions of these CLRs are complex, and their roles in diseases, their ligands, and the detailed mechanisms underlying their actions remain largely unknown. Elucidation of the physiological as well as pathological roles of these CLRs may provide us with clues that could aid in the development of new therapeutics against these diseases.

AUTHORSHIP
C.T. and Y.M. are co-first authors of the study.

DISCLOSURE
The authors declare no conflict of interest.