Collectin 11 has a pivotal role in host defense against kidney and bladder infection in mice.

The urinary tract is constantly exposed to microorganisms. Host defense mechanisms in protection from microbial colonization and development of urinary tract infections require better understanding to control kidney infection. Here we report that the lectin collectin 11 (CL-11), particularly kidney produced, has a pivotal role in host defense against uropathogen infection. CL-11 was found in mouse urine under normal and pathological conditions. Mice with global gene ablation of Colec11 had increased susceptibility to and severity of kidney and to an extent, bladder infection. Mice with kidney-specific Colec11 ablation exhibited a similar disease phenotype to that observed in global Colec11 deficient mice, indicating the importance of kidney produced CL-11 for protection against kidney and bladder infection. Conversely, intravesical or systemic administration of recombinant CL-11 reduced susceptibility to and severity of kidney and bladder infection. Mechanism analysis revealed that CL-11 can mediate several key innate defense mechanisms (agglutination, anti- adhesion, opsonophagocytosis), and limit local inflammatory responses to pathogens. Furthermore, CL-11-mediated innate defense mechanisms can act on clinically relevant microorganisms including multiple antibiotic resistant strains. CL-11 was detectable in eight of 24 urine samples from patients with urinary tract infections but not detectable in urine samples from ten healthy individuals. Thus, our findings demonstrate that CL-11 is a key factor of host defense mechanisms in kidney and bladder infection with therapeutic potential for human application.

Vitamin D3 enhances the antibacterial ability in head-kidney macrophages of turbot (Scophthalmus maximus L.) through C-type lectin receptors.

It has been known that vitamin D3 (VD3) not only plays an important role in regulating calcium and phosphorus metabolism in animals, but also has extensive effects on immune functions. In this study, the mechanism how VD3 influences bactericidal ability in turbot was explored. The transcriptomic analysis identified that dietary VD3 significantly upregulated the gene expression of C-type lectin receptors (CLRs), including mannose receptors (mrc1, mrc2, pla2r1) and collectins (collectin 11 and collectin 12) in turbot intestine. Further results obtained from in vitro experiments confirmed that the gene expression of mannose receptors and collectins in head-kidney macrophages (HKMs) of turbot was induced after the cells were incubated with different concentrations of VD3 (0, 1, 10 nM) or 1,25(OH)2D3 (0, 10, 100 pM). Meanwhile, both phagocytosis and bactericidal functions of HKMs were significantly improved in VD3 or 1,25(OH)2D3-incubated HKMs. Furthermore, phagocytosis and bacterial killing of HKMs decreased after collectin 11 was knocked down. Moreover, VD3-enhanced antibacterial activities diminished in collectin 11-interfered cells. Interestingly, the evidence was provided in the present study that inactive VD3 could be metabolized into active 1,25(OH)2D3 via hydroxylases encoded by cyp27a1 and cyp27b1 in fish macrophages. In conclusion, VD3 could be metabolized to 1,25(OH)2D3 in HKMs, which promoted the expression of CLRs in macrophages, leading to enhanced bacterial clearance.

Identification and functional characterization of CL-11 in black rockfish (Sebastes schlegelii).

CL-11 (Collectin-11, also known as Collectin kidney-1 or CL-K1) is a member of collectin family that works as a pattern recognition molecule (PRM) and participating in lectin-complement pathway in host defense against pathogens. We identified the CL-11 homologue SsCL-11 in black rockfish (Sebastes schlegelii) and investigated the functional characteristics in this study. The SsCL-11 has conserved protein modules, i.e. an N-terminal hydrophobic region, a collagen-like region, an α-helical neck region and a carbohydrate recognition domain (CRD). SsCL-11 has varying degrees of expressions in difference tissues, among which the highest expression is observed in liver. It also shows induced expressions in immune-related tissues following Aeromonas salmonicida (A. salmonicida) infection. In addition, SsCL-11 exhibits binding abilities to different kinds of carbohydrates, pathogen-associated molecular patterns (PAMPs) and bacteria. It exhibits comparatively strong binding to l-fucose, d-mannose, and d-glucose, which is consistent with the functional EPN motif in its CRD. SsCL-11 also shows agglutinating effects on various bacteria in the presence of Ca2+. Furthermore, SsCL-11 is confirmed to be a secretory lectin and can form multimers. These findings collectively demonstrate that SsCL-11 can function as a recognition molecule in pathogen resistance in black rockfish, which will promote our understanding of immunological roles of fish collectins.

l-Fucose prevention of renal ischaemia/reperfusion injury in Mice.

In a recent study, we identified a fucosylated damage-associated ligand exposed by ischemia on renal tubule epithelial cells, which after recognition by collectin-11 (CL-11 or collectin kidney 1 (CL-K1)), initiates complement activation and acute kidney injury. We exploited the ability to increase the local tissue concentration of free l-fucose following systemic administration, in order to block ligand binding by local CL-11 and prevent complement activation. We achieved a thirty-five-fold increase in the intrarenal concentration of l-fucose following an IP bolus given before the ischemia induction procedure - a concentration found to significantly block in vitro binding of CL-11 on hypoxia-stressed renal tubule cells. At this l-fucose dose, complement activation and acute post-ischemic kidney injury are prevented, with additional protection achieved by a second bolus after the induction procedure. CL-11-/- mice gained no additional protection from l-fucose administration, indicating that the mechanism of l-fucose therapy was largely CL-11-dependent. The hypothesis is that a high dose of l-fucose delivered to the kidney obstructs the carbohydrate recognition site on CL-11 thereby reducing complement-mediated damage following ischemic insult. Further work will examine the utility in preventing post-ischemic injury during renal transplantation, where acute kidney injury is known to correlate with poor graft survival.

Fucose as a new therapeutic target in renal transplantation.

Ischaemia/reperfusion injury (IRI) is an inevitable and damaging consequence of the process of kidney transplantation, ultimately leading to delayed graft function and increased risk of graft loss. A key driver of this adverse reaction in kidneys is activation of the complement system, an important part of the innate immune system. This activation causes deposition of complement C3 on renal tubules as well as infiltration of immune cells and ultimately damage to the tubules resulting in reduced kidney function. Collectin-11 (CL-11) is a pattern recognition molecule of the lectin pathway of complement. CL-11 binds to a ligand that is exposed on the renal tubules by the stress caused by IRI, and through attached proteases, CL-11 activates complement and this contributes to the consequences outlined above. Recent work in our lab has shown that this damage-associated ligand contains a fucose residue that aids CL-11 binding and promotes complement activation. In this review, we will discuss the clinical context of renal transplantation, the relevance of the complement system in IRI, and outline the evidence for the role of CL-11 binding to a fucosylated ligand in IRI as well as its downstream effects. Finally, we will detail the simple but elegant theory that increasing the level of free fucose in the kidney acts as a decoy molecule, greatly reducing the clinical consequences of IRI mediated by CL-11.

Importance of glycosylation in the interaction of Tamm-Horsfall protein with collectin-11 and acute kidney injury.

Both Tamm-Horsfall protein (THP) and collectin-11 (CL-11) are important molecules in acute kidney injury (AKI). In this study, we measured the change of glycosylation of THP in patients with AKI after surgery, using MALDI-TOF MS and lectin array analysis. The amount of high-mannose and core fucosylation in patients with AKI were higher than those in healthy controls. In vitro study showed that THP could bind to CL-11 with affinity at 9.41 × 10-7  mol/L and inhibited activation of complement lectin pathway. The binding affinity decreased after removal of glycans on THP. Removal of fucose completely ablated the binding between the two proteins. While removal of high-mannose or part of the N-glycan decreased the binding ability to 30% or 60%. The results indicated that increase of fucose on THP played an important role via complement lectin pathway in AKI.

Initiators of Classical and Lectin Complement Pathways Are Differently Engaged after Traumatic Brain Injury-Time-Dependent Changes in the Cortex, Striatum, Thalamus and Hippocampus in a Mouse Model.

The complement system is involved in promoting secondary injury after traumatic brain injury (TBI), but the roles of the classical and lectin pathways leading to complement activation need to be clarified. To this end, we aimed to determine the ability of the brain to activate the synthesis of classical and lectin pathway initiators in response to TBI and to examine their expression in primary microglial cell cultures. We have modeled TBI in mice by controlled cortical impact (CCI), a clinically relevant experimental model. Using Real-time quantitative polymerase chain reaction (RT-qPCR) we analyzed the expression of initiators of classical the complement component 1q, 1r and 1s (C1q, C1r, and C1s) and lectin (mannose binding lectin A, mannose binding lectin C, collectin 11, ficolin A, and ficolin B) complement pathways and other cellular markers in four brain areas (cortex, striatum, thalamus and hippocampus) of mice exposed to CCI from 24 h and up to 5 weeks. In all murine ipsilateral brain structures assessed, we detected long-lasting, time- and area-dependent significant increases in the mRNA levels of all classical (C1q, C1s, C1r) and some lectin (collectin 11, ficolin A, ficolin B) initiator molecules after TBI. In parallel, we observed significantly enhanced expression of cellular markers for neutrophils (Cd177), T cells (Cd8), astrocytes (glial fibrillary acidic protein-GFAP), microglia/macrophages (allograft inflammatory factor 1-IBA-1), and microglia (transmembrane protein 119-TMEM119); moreover, we detected astrocytes (GFAP) and microglia/macrophages (IBA-1) protein level strong upregulation in all analyzed brain areas. Further, the results obtained in primary microglial cell cultures suggested that these cells may be largely responsible for the biosynthesis of classical pathway initiators. However, microglia are unlikely to be responsible for the production of the lectin pathway initiators. Immunofluorescence analysis confirmed that at the site of brain injury, the C1q is localized in microglia/macrophages and neurons but not in astroglial cells. In sum, the brain strongly reacts to TBI by activating the local synthesis of classical and lectin complement pathway activators. Thus, the brain responds to TBI with a strong, widespread and persistent upregulation of complement components, the targeting of which may provide protection in TBI.

Identification, expression profile and analysis of the antimicrobial activity of collectin 11 (CL-11, CL-K1), a novel complement-associated pattern recognition molecule, in half-smooth tongue sole (Cynoglossus semilaevis).

Collectin 11 (CL-11, also known as collectin kidney-1, CL-K1), a new member of the vertebrate C-type lectin superfamily, plays an important role in innate immunity as a pattern recognition molecule of the lectin complement pathway. However, little is known about CL-11 in teleosts. In the present study, a CL-11 homolog was identified and characterized from half-smooth tongue sole (Cynoglossus semilaevis) (designated as CsCL-11). The full-length cDNA of CsCL-11 is 1220 bp long and includes a 5'untranslated region (5'-UTR) of 180 bp, a 3'-UTR of 218 bp and an open reading frame (ORF) of 819 bp encoding 273 amino acids. Multiple sequence alignment revealed that the deduced CsCL-11 protein has the typical modular architecture (EPN and WTD) conserved throughout vertebrates, suggesting a conserved function of CsCL-11. Tissue expression profile analysis by quantitative real-time PCR (qRT-PCR) showed CsCL-11 to be ubiquitously distributed in tissues and highly expressed in the ovary and liver. A pattern of significant upregulation of CsCL-11 expression was observed in the blood, spleen, head kidney and gill at 6 h, 12 h and 24 h after infection with Vibrio anguillarum, and western blotting showed that natural CsCL-11 protein levels in the blood were significantly increased after V. anguillarum infection. Moreover, by binding to various bacteria, recombinant CsCL-11 (rCsCL-11) expressed in HEK-293 T cells displayed strong antibacterial activity. Taken together, these results suggest that CsCL-11 is a unique C-type lectin that is likely involved in host defense against bacterial infection. To our knowledge, this is the first study on CL-11 in marine fish.

Collectin-11 Promotes the Development of Renal Tubulointerstitial Fibrosis.

Collectin-11 is a recently described soluble C-type lectin, a pattern recognition molecule of the innate immune system that has distinct roles in host defense, embryonic development, and acute inflammation. However, little is known regarding the role of collectin-11 in tissue fibrosis. Here, we investigated collectin-11 in the context of renal ischemia-reperfusion injury. Compared with wild-type littermate controls, Collec11 deficient (CL-11-/- ) mice had significantly reduced renal functional impairment, tubular injury, renal leukocyte infiltration, renal tissue inflammation/fibrogenesis, and collagen deposition in the kidneys after renal ischemia-reperfusion injury. In vitro, recombinant collectin-11 potently promoted leukocyte migration and renal fibroblast proliferation in a carbohydrate-dependent manner. Additionally, compared with wild-type kidney grafts, CL-11-/-mice kidney grafts displayed significantly reduced tubular injury and collagen deposition after syngeneic kidney transplant. Our findings demonstrate a pathogenic role for collectin-11 in the development of tubulointerstitial fibrosis and suggest that local collectin-11 promotes this fibrosis through effects on leukocyte chemotaxis and renal fibroblast proliferation. This insight into the pathogenesis of tubulointerstitial fibrosis may have implications for CKD mediated by other causes as well.

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

BACKGROUND/AIMS: Complement activation is important in post-transplantation renal injury, but data on its role as predictor of transplant outcome/complications when assessed in donor kidneys are lacking. METHODS: In human renal transplant biopsies with delayed graft function (DGF, n=12), antibody mediated rejection (ABMR, n=8), T-cell mediated rejection (TCMR, n=11), 1 year protocol biopsies (control, n=10) and corresponding zero-biopsies we performed immunohistochemical analyses of 6 complement factors using FFPE sections and correlated the findings with kidney function, as assessed by serum creatinine, and morphological changes including interstitial fibrosis and tubular atrophy (IF/TA). RESULTS: In DGF, TCMR and ABMR significant complement deposition was observed, which was less pronounced in corresponding zero-biopsies. Zero-biopsies with subsequent ABMR showed glomerular complement factor D and C3c expression. Moreover, glomerular C3c and C9 and tubular MASP-2 and Collectin-11 expression in zero-biopsies significantly correlated with serum creatinine at diagnosis of DGF, TCMR or ABMR. Glomerular C1q was significantly increased in ABMR, but not in DGF and TCMR. In contrast, peritubular C1q was significantly enhanced in DGF and TCMR compared to zero-biopsies. Using C3d as a surrogate marker for complement activity we could confirm that stained complement factors are frequently associated with complement activity. CONCLUSION: Complement deposition strongly correlated with histopathological changes observed in renal transplants. All 3 complement pathways were operational in biopsies with DGF, TCMR and ABMR albeit with differential abundance and localization. Since complement deposition in zero-biopsies correlated with graft function and morphological changes, early specific complement inhibition in renal transplantation may be a new therapeutic option to prevent graft loss.

Complement Recognition Pathways in Renal Transplantation.

The complement system, consisting of soluble and cell membrane-bound components of the innate immune system, has defined roles in the pathophysiology of renal allograft rejection. Notably, the unavoidable ischemia-reperfusion injury inherent to transplantation is mediated through the terminal complement activation products C5a and C5b-9. Furthermore, biologically active fragments C3a and C5a, produced during complement activation, can modulate both antigen presentation and T cell priming, ultimately leading to allograft rejection. Earlier work identified renal tubule cell synthesis of C3, rather than hepatic synthesis of C3, as the primary source of C3 driving these effects. Recent efforts have focused on identifying the local triggers of complement activation. Collectin-11, a soluble C-type lectin expressed in renal tissue, has been implicated as an important trigger of complement activation in renal tissue. In particular, collectin-11 has been shown to engage L-fucose at sites of ischemic stress, activating the lectin complement pathway and directing the innate immune response to the distressed renal tubule. The interface between collectin-11 and L-fucose, in both the recipient and the allograft, is an attractive target for therapies intended to curtail renal inflammation in the acute phase.

The lectin pathway of complement: advantage or disadvantage in HIV pathogenesis?

The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity.

Soluble Collectin 11 (CL-11) Acts as an Immunosuppressive Molecule Potentially Used by Stem Cell-Derived Retinal Epithelial Cells to Modulate T Cell Response.

Retinal pigment epithelium (RPE) cell allotransplantation is seen as a possible solution to retinal diseases. However, the RPE-complement system triggered by the binding of collectin-11 (CL-11) is a potential barrier for RPE transplantation as the complement-mediated inflammatory response may promote T cell recognition. To address this, we investigated the role of CL-11 on T cell immuno-response. We confirmed that RPE cells up-regulated MHC class I and expressed MHC class II molecules in an inflammatory setting. Co-cultures of RPE cells with T cells led to the inhibition of T cell proliferation. We found that CL-11 was partially responsible for this effect as T cell binding of CL-11 inhibited T cell proliferation in association with the downregulation of CD28. We also found that the suppressive action of CL-11 was abrogated in the presence of the RGD peptide given to block the T cell binding of CL-11 by its collagen-like domain. Because RPE cells can bind and secrete CL-11 under stress conditions, we postulate that soluble CL-11 contributes to the immunosuppressive properties of RPE cells. The investigation of this dual biological activity of CL-11, namely as a trigger of the complement cascade and a modulator of T cell responses, may provide additional clues about the mechanisms that orchestrate the immunogenic properties of RPE cells.

Role of collectin-11 in innate defence against uropathogenic Escherichia coli infection.

Classical collectins (surfactant protein A and D) play a significant role in innate immunity and host defence in uropathogenic Escherichia coli (UPEC)-induced urinary tract infection (UTI). However, the functions of collectin-11 (CL-11) with respect to UPEC and UTI remain largely unexplored. This study aimed to investigate the effect of CL-11 on UPEC and its role in UTI. We further examined its modulatory effect on inflammatory reactions in proximal tubular epithelial cells (PTECs). The present study provides evidence for the effect of CL-11 on the growth, agglutination, binding, epithelial adhesion and invasion of UPEC. We found increased basal levels of phosphorylated p38 MAPK and human cytokine homologue (keratinocyte-derived chemokine) expression in CL-11 knockdown PTECs. Furthermore, signal regulatory protein α blockade reversed the increased basal levels of inflammation associated with CL-11 knockdown in PTECs. Additionally, CL-11 knockdown effectively inhibited UPEC-induced p38 MAPK phosphorylation and cytokine production in PTECs. These were further inhibited by CD91 blockade. We conclude that CL-11 functions as a mediator of innate immunity via direct antibacterial roles as well as dual modulatory roles in UPEC-induced inflammatory responses during UTI. Thus, the study findings suggest a possible function for CL-11 in defence against UTI.

Molecular characterization and complement activating functional analysis of a new collectin(TfCol-11) from Trachidermus fasciatus.

The complement system is a crucial component of the innate immune system that links innate and adaptive immunity. CL-11, a protein similar to Mannose-binding lectin (MBL), plays significant role in the innate immune system in mammals and fish, serving as an initiator of the lectin pathway of complement activation. In this study, a CL-11 homolog (TfCol-11) was identified in roughskin sculpin (Trachidermus fasciatus), and its expression and role in immune responses were characterized. The open reading frame of TfCol-11 is 795 bp long, encoding a 264 amino acid polypeptide. The deduced amino acid sequence of this protein is highly homologous to sequences in other teleosts, and is similar to vertebrate CL-11, containing a canonical collagen-like region, a carbohydrate recognition domain, and a neck region. Recombinant TfCol-11 purified from Escherichia coli(E.coli) was able to bind to different microbes in a Ca2+-independent manner. Meanwhile, a 993 bp-long of partial MASP cDNA with a 96 bp 5' untranslated region (UTR) was also cloned from roughskin sculpin, containing 299 amino acids and consisting of three domains (CUB-EGF-CUB). qRT-PCR indicated that TfCol-11 and MASP mRNAs were predominately co-expressed in the liver. The temporal expression of TfCol-11 and MASP were both drastically up-regulated in the liver, skin, and blood by LPS challenge. Recombinant TfCol-11 purified from E.coli BL21(DE3) was able to agglutinate some bacteria in a Ca2+-dependent manner. In addition, an in vitro pull-down experiment demonstrated that TfCol-11 was able to bind to MASP, and in vivo experiments showed that TfCol-11 was associated with increased membrane attack complex (MAC) levels. It is therefore possible that TfCol-11 may plays a role in activating the complement system and in the defense against invading microorganisms in roughskin sculpin.

Complement related pattern recognition molecules as markers of short-term mortality in intensive care patients.

OBJECTIVES: To evaluate the complement related pattern recognition molecules (PRMs) PTX3, MBL, CL-11, ficolin-2 and -3, along with the established marker CRP, to predict 28-day mortality and disease severity of sepsis in patients admitted to the intensive care unit (ICU). METHODS: In a single-center, prospective, observational study 547 patients were included over a period of 18 months. Blood samples were obtained at admission to the ICU and the following 4 days. RESULTS: PTX3 baseline levels were significantly higher in non-survivors compared to survivors, whereas MBL and ficolin-2 levels were significantly lower in non-survivors compared to survivors. A PTX3 level above the median was independently associated with 28-day mortality in the adjusted analysis including age, sex, chronic disease and immunosuppression (HR 1.87, 95% CI [1.41-2.48], p < 0.0001), while a MBL level above the median was associated with increased chance of survival (HR 0.75, 95% CI [0.57-0.98], p = 0.034). Ficolin-2 was only borderline significant (HR 0.79, 95% CI [0.60-1.03], p = 0.084). In a ROC analysis PTX3 was superior to CRP in predicting septic shock. CONCLUSIONS: PTX3, MBL and CRP levels were independently associated with 28-day mortality in ICU patients. PTX3 was a better marker of septic shock compared to CRP.

Structural and functional diversity of collectins and ficolins and their relationship to disease.

Pattern recognition molecules are sensors for the innate immune system and trigger a number of pathophysiological functions after interaction with the corresponding ligands on microorganisms or altered mammalian cells. Of those pattern recognition molecules used by the complement system, collagen-like lectins (collectins) are an important subcomponent. Whereas the best known of these collectins, mannose-binding lectin, largely occurs as a circulating protein following production by hepatocytes, the most recently described collectins exhibit strong local biosynthesis. This local production and release of soluble collectin molecules appear to serve local tissue functions at extravascular sites, including a developmental function. In this article, we focus on the characteristics of collectin-11 (CL-11 or CL-K1), whose ubiquitous expression and multiple activities likely reflect a wide biological relevance. Collectin-11 appears to behave as an acute phase protein whose production associated with metabolic and physical stress results in locally targeted inflammation and tissue cell death. Early results indicate the importance of fucosylated ligand marking the injured cells targeted by collectin-11, and we suggest that further characterisation of this and related ligands will lead to better understanding of pathophysiological significance and exploitation for clinical benefit.

Collectins in urinary tract and kidney diseases.

The innate immune system serves as the frontline defense against invading pathogens and initiates an inflammatory response to microorganisms. Collectins are C-type lectins that are structurally characterized by a collagen-like sequence and a carbohydrate recognition domain. Moreover, they are widely expressed throughout the body and are involved in the innate immunity against a variety of pathogens, regulating inflammation, and protecting the lungs from pathogens. Recently, two classical collectins, surfactant protein A (SP-A) and surfactant protein D (SP-D), as well as novel collectin 11, were found present in urinary tract tissues. They are increasingly recognized as key players in activating the humoral arm of innate immunity and host defense in urinary tract and kidney diseases, although their biological features, functions, and mechanisms in this regard remain largely unclear. In this review, we aim to integrate results reported by ourselves and others to summarize and gain a better understanding of the functions of collectins (SP-A, SP-D, and collectin 11) in urinary tract and kidney diseases.

Collectin-11 (CL-11) Is a Major Sentinel at Epithelial Surfaces and Key Pattern Recognition Molecule in Complement-Mediated Ischaemic Injury.

The complement system is a dynamic subset of the innate immune system, playing roles in host defense, clearance of immune complexes and cell debris, and priming the adaptive immune response. Over the last 40 years our understanding of the complement system has evolved from identifying its presence and recognizing its role in the blood to now focusing on understanding the role of local complement synthesis in health and disease. In particular, the local synthesis of complement was found to have an involvement in mediating ischaemic injury, including following transplantation. Recent work on elucidating the triggers of local complement synthesis and activation in renal tissue have led to the finding that Collectin-11 (CL-11) engages with L-fucose at the site of ischaemic stress, namely at the surface of the proximal tubular epithelial cells. What remains unknown is the precise structure of the damage-associated ligand that participates in CL-11 binding and subsequent complement activation. In this article, we will discuss our hypothesis regarding the role of CL-11 as an integral tissue-based pattern recognition molecule which we postulate has a significant contributory role in complement-mediated ischaemic injury.

Collectin-11 Is an Important Modulator of Retinal Pigment Epithelial Cell Phagocytosis and Cytokine Production.

In this paper, we report previously unknown roles for collectin-11 (CL-11, a soluble C-type lectin) in modulating the retinal pigment epithelial (RPE) cell functions of phagocytosis and cytokine production. We found that CL-11 and its carbohydrate ligand are expressed in both the murine and human neural retina; these resemble each other in terms of RPE and photoreceptor cells. Functional analysis of murine RPE cells showed that CL-11 facilitates the opsonophagocytosis of photoreceptor outer segments and apoptotic cells, and also upregulates IL-10 production. Mechanistic analysis revealed that calreticulin on the RPE cells is required for CL-11-mediated opsonophagocytosis whereas signal-regulatory protein α and mannosyl residues on the cells are involved in the CL-11-mediated upregulation of IL-10 production. This study is the first to demonstrate the role of CL-11 and the molecular mechanisms involved in modulating RPE cell phagocytosis and cytokine production. It provides a new insight into retinal health and disease and has implications for other phagocytic cells.