Atopic Dermatitis and C-Type Lectin Receptors

Atopic dermatitis is a chronic skin disease caused by specific allergens. The main symptoms are pruritus, rash, dry skin, and hyperpigmentation of the affected areas. Severe itching causes difficulty concentrating and interferes with many aspects of daily life, thus decreasing quality of life. Atopic dermatitis is highly prevalent in children, with 20% of children and 10% of adults in developed countries reportedly affected. Currently, the main treatment for atopic dermatitis is alleviating symptoms with immunosuppressive drugs, including steroids and antibody drugs (1).

Atopic dermatitis is caused by an abnormal immune response in the skin to allergens. It has been reported that 30-70% of patients with atopic dermatitis are positive for house dust mite (HDM) in patch tests (2). HDM is found in hot and humid environments such as bedding, sofas, and carpets, and their carcasses and feces can trigger allergic reactions. HDMs are known to be capable of inducing allergic reactions to a variety of substances, including insect chitin, β-glucans, lipopolysaccharides (LPS), and serine proteases, which stimulate pattern recognition receptors (PRRs) on immune cells in the form of pathogen-associated molecular patterns (PAMPs). Innate immune cells such as neutrophils, macrophages, and dendritic cells recognize PAMPs via Toll-like receptors (TLRs) as PRRs, thereby producing proinflammatory cytokines and chemokines, which induce acute dermatitis (Figure 1) (3). C-type lectin receptors (CLRs), also one of the PRRs, recognize glycan structures of pathogens, including HDMs and bacteria; CLRs regulate innate immune cell activity via intracellular signaling, and some CLRs can activate tyrosine phosphatase-1/2 (SHP-1/2) to suppress inflammatory responses (Figure 2). This phenomenon suppresses excessive immune responses in mucosal tissues and skin and plays an important role in tissue homeostasis (4).

Figure 1. Induction of proinflammatory signals by HDM The downstream signal of TLRs induced by HDM activates the transcription factors such as NF-κB, MAPK, and IRFs. These transcription factors promote transcriptions of inflammatory cytokines and chemokine. These responses exacerbate the symptoms of atopic dermatitis.

Figure 2. Immunological functions of C-type lectin receptors ITAM on the intracellular domain of the CLRs promotes immune activity, whereas ITIM suppresses immune activity. HemITAM has either activating or inhibitory functions. These amino acid sequences are tyrosine phosphorylated after glycan ligand binding to the carbohydrate recognition domain and activate downstream signaling molecules such as Syk and SHP-1/2. Some CLRs augment or attenuate the downstream signal of PRRs such as TLRs. However, it remains elusive how CLRs suppress the downstream signaling of TLRs with SHP-1/2.

In recent years, the link between CLRs and various diseases has been revealed one after another (4). For example, it was reported that in mice lacking the gene for Dectin-2, one of the CLRs, the phagocytosis of tumor cells inoculated into the spleen by intrahepatic Kupffer cells is reduced compared to wild-type mice (5). This indicates that Dectin-2 on Kupffer cells in the liver promotes phagocytosis of tumor cells and suppresses liver metastasis. It has also been reported that Clec2 expressed on platelets promotes platelet aggregation and suppresses growth factor release, angiogenesis, and immune activity by associating with podoplanin produced by tumor cells (6). On the other hand, in relation to autoimmune diseases and allergic reactions, polymorphisms of dendritic cell immune receptor (DCIR) have been reported to correlate with susceptibility to rheumatoid arthritis (7). DCIR inhibits excessive activation of dendritic cells via SHP-1, a tyrosine phosphatase, but genetic deletion of DCIR mice also showed increased activation of dendritic cells and spontaneous development of autoimmune inflammation (8). Dectin-1 expressed on epithelial cells in the nasal cavity and bronchioles has also been reported to suppress the production of a cytokine called interleukin-33 when it recognizes tropomyosin from arthropods, thereby suppressing allergic reactions (9). The authors have also reported that a CLR expressed on macrophages, Clec10a, a CLR expressed on macrophages, suppresses atopic dermatitis induced by HDM (Figure 3) (10). Skin macrophages recognized HDM-derived mucin-like molecules via Clec10a, and as a result, activated Clec10a suppressed downstream signaling of TLR4 activated by HDM, which reduced the production of inflammatory cytokines and chemokines and palliated HDM-induced dermatitis. Furthermore, we found that the human counterpart of mouse Clec10a is human asialoglycoprotein receptor 1 (hASGR1), and knockdown of hASGR1 expressed on macrophages increased HDM-induced cytokine production, indicating that hASGR1 has a function similar to that of mouse Clec10a.

As described above, the relationship between CLR and various diseases, including allergy, has recently been clarified, and basic and clinical research aimed at developing molecular-targeted drugs for CLR is an area that is expected to develop further in the future.

Figure 3. Schematic abstract of mouse Clec10a function on skin macrophage (Partly modified from Sci Immunol, 2019;4:eaax6908) The intracellular domain of mouse Clec10a harbors hemITAM, which activates SHP-1. The SHP-1 suppresses the downstream signal of TLR4, which is stimulated by other PAMPs derived from HDM. After that, inflammatory responses by skin macrophages are attenuated, and HDM-induced dermatitis is suppressed.

Katsunobu Shigematsu
(Department of Immunology, Faculty of Medicine, University of Tsukuba; Ph. D. Program in Humanics, University of Tsukuba)

Akira Shibuya
(Department of Immunology, Faculty of Medicine, University of Tsukuba; R&D Center for Innovative Drug Discovery, University of Tsukuba)

Jun. 15, 2023