A Plausible Role for Collectins in Skin Immune Homeostasis

Abstract

The skin is a complex organ that faces the external environment and participates in the innate immune system. Skin immune homeostasis is necessary to defend against external microorganisms and to recover from stress to the skin. This homeostasis depends on interactions among a variety of cells, cytokines, and the complement system. Collectins belong to the lectin pathway of the complement system, and have various roles in innate immune responses. Mannose-binding lectin (MBL), collectin kidney 1, and liver (CL-K1, CL-L1) activate the lectin pathway, while all have multiple functions, including recognition of pathogens, opsonization of phagocytosis, and modulation of cytokine-mediated inflammatory responses. Certain collectins are localized in the skin, and their expressions change during skin diseases. In this review, we summarize important advances in our understanding of how MBL, surfactant proteins A and D, CL-L1, and CL-K1 function in skin immune homeostasis. Based on the potential roles of collectins in skin diseases, we suggest therapeutic strategies for skin diseases through the targeting of collectins and relevant regulators.

Keywords: collectins; immune homeostasis; immunity; immunotherapy; skin.

Figure 1

Cells, cytokines, and the complement system are involved in skin homeostasis. Keratinocytes recognize pathogen-associated molecular patterns via pattern recognition receptors on their surfaces, and they secrete antimicrobial peptides. Fibroblasts secrete C3b, C5a, and MAC, which are involved in pathogen clearance by complement. Langerhans cells are antigen-presenting cells for microbial antigens in the epidermis. Dendritic cells secret most components of complement system and mediate together with macrophages pahgocytosis of pathogens via complement receptors (CR1, CR3 and CR4). They could mediate phagocytosis in the clearance of pathogens by receptors (e.g., C3R, C4R) on their surface in turn. Macrophages participate in inflammation and wound repair. Receptors for C3a on mast cells can be activated by their ligands to degranulate and secret cytokines including MCP-1 and RANTES, which participate in wound repair. Pathogens stimulate collectins to activate complement system. Collectins may also modulate inflammation by macrophages and DCs directly. Keratinocytes recruit αβ T cells, and γδ T cells to epidermis. AMP, antimicrobial peptide; PRR, pattern recognition receptor; APC, antigen-presenting cell; DC, dendritic cells.

Figure 2

Lectin pathway and alternative pathway of the complement system. Collectins (including MBL, CL-L1, CL-K1 and the complex of the latter CL-LK complex) recognize carbohydrates on surface of pathogens and activate the lectin pathway via MASP-1 and MASP-2. The alternative pathway is activated by spontaneous hydrolysis of C3. Factor D is a rate limiting factor for generation of the C3 convertase in the alternative pathway, which is activated by MASP-3. The alternative pathway works as an amplification loop for the lectin pathway.

Figure 3

Collectins are constructed of four domains: an N-terminal cysteine-rich segment, a collagen-like region, a neck region and a C terminal carbohydrate recognition domain (CRD). MBL usually forms trimers to hexamers. CL-K1 forms dimers and trimers of trimeric subunits. SP-A and SP-D are mainly hexamers and cruciform tetramers. The subunit of CL-LK are formed by two CL-K1 and one CL-L1 approximately.

Figure 4

Functions of collectins in skin immune homeostasis. Collectins are similar in structure in terms of their carbohydrate recognition domains, collagen-like, and N-terminal regions. MBL and CL-K1 recognize microorganisms and activate the lectin pathway to clear pathogens. SP-A and SP-D can bind to microorganisms directly and cause aggregation. CL-L1 might initiate the lectin pathway by forming CL-LK with CL-K1. MBL, SP-A, and SP-D can recognize DNA from apoptotic cells and mediate the uptake of apoptotic cells. SP-A and SP-D also suppress apoptotic cell clearance by binding SIRP-α on macrophages (black arrows). MBL promotes keratinocytes to produce chemokine (C-X-C motif) ligand 1 to increase neutrophil infiltration. Surfactant proteins might induce the production of TNF-α via macrophages. SP-A and SP-D can bind to SIRP-α on macrophages and epithelia through their globular heads to suppress inflammation (black arrows). CL-K1 may modulate the production of IL-6 and IL-10 by fibroblasts. CL-K1 and CL-L1 may influence the function of melanocytes by affecting the immigration of neural crest cells. Clearance of pathogens rely on the participation of inflammatory cells and cytokines, and inflammatory responses lead to immune cells undergoing apoptosis. In reverse, accumulation of apoptotic cells can cause inflammation. And dysfunction of skin caused by inflammation results in inability of pathogens clearance. Thus, skin infectious diseases, inflammatory diseases and autoimmune diseases interact tightly with each other. The solid lines represent known functions, while dashed lines represent speculations.

Figure 5

Immunohistochemistry of MBL, SP-A, and SP-D in normal human tissues. (A) MBL in the liver (DAB staining with MBL2 polyclonal antibody, 40×). (B) MBL in the liver (MBL2 polyclonal antibody, 200×). (C) MBL in the skin (MBL2 polyclonal antibody, 400×). (D) SP-A in the skin (SFTPA1 polyclonal antibody, 400×). (E) SP-D in the skin (Hyb 245-1,400×). (F) SP-D in psoriasis lesions (monoclonal antibody Hyb 245-1, 400×). (G) SP-D in atopic dermatitis (monoclonal antibody Hyb 245-1, 400×). (H) Deposition of MBL in the basal membrane zone with granular pattern by immunofluorescence. Panel (E) was modified and reprinted from Madsen, et al. in 2015 (43). Panel (F, G) are modified and reprinted from Hohwy, et al. in 2006 (44). Panel (H) was modified and reprinted from Wallim LR et al. in 2014 (45).

Figure 6

Immunohistochemical localization of CL-K1 and CL-L1 in formalin-fixed and paraffin-embedded sections of kidney, liver, and skin. (A) CL-K1 in the kidney. (B) CL-L1 in the liver. (C) CL-K1 in the skin. (D) CL-L1 in the skin. Italic letters within the images refer to: 1) h: hepatocytes, ch: centrilobular hepatocytes, and kc: Kupffer cells for the liver; 2) g: glomerulus for the kidney; and 3) ed: epidermis, de: dermis, hd: hypodermis, sg: sweat glands, me: myoepithelial cells, and se: stratified cuboidal epithelia cells for the skin. This figure is modified and reprinted from Hansen, et al. in 2018 (36). Scale bars in large sections correspond to 500 μm and in small sections to 50 μm.