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. Author manuscript; available in PMC: 2023 Jun 1.
Published in final edited form as: Transpl Immunol. 2022 Mar 11;72:101580. doi: 10.1016/j.trim.2022.101580

CD14 blockade to prevent ischemic injury to donor organs

Jason Own a,c, Richard Ulevitch a, Dianne McKay a,b
PMCID: PMC9762458  NIHMSID: NIHMS1791427  PMID: 35283329

Abstract

The purpose of this review is to highlight the potential role for the cluster of differentiation protein 14 (CD14), a co-receptor for toll-like receptor (TLR) signals and as a proximal target for innate immune signals induced during procurement of solid organs for transplantation. CD14 facilitates the detection of multiple pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by various TLRs. All solid organs used for transplantation are exposed to PAMPs and DAMPs generated during the course of procurement that inevitably trigger injurious inflammatory responses in the donor organ.

Multiple experimental animal studies and observations in human organs have provided a solid rationale to consider CD14 blockade as a therapeutic target. CD14 has been recognized for over three decades to play an essential role in innate immune signals associated with sepsis. More recent data now show that genetic deletion or antibody blockade of CD14 can modify ischemic tissue injury in the kidney, liver, heart and lung. Thus, data presented in this review suggest that anti-CD14 directed therapies might be applied to organ preservation strategies in solid organ transplantation.

Keywords: Toll-like receptor, cluster of differentiation 4, pattern recognition receptor, ischemia reperfusion injury, transplantation

Introduction

Mechanism of CD14 activity

The innate immune system is a rapid defense system triggered by molecules released by pathogens (pathogen associated molecular patterns, PAMPs) and host tissue (damage associated molecular patterns, DAMPs). Host defense responses are triggered by PAMP or DAMP molecules that ligate pattern recognition receptors (PRRs) on immune and parenchymal cells. PRRs are expressed on many cell types and the best studied are the membrane-bound Toll-like receptors (TLRs) and the cytoplasmic nucleotide-binding oligomerization domain-like receptors (NLRs).

Accessory proteins are needed for TLRs to optimally respond to PAMPs and DAMPs. CD14 is a key accessory protein that allows PAMPs and DAMPs to be detected by TLRs. In the case of TLR4, LPS aggregates are extracted and monomerized by the acute phase reactant LPS-binding protein (LBP) (Figure 1). LBP transfers LPS to CD14, allowing CD14 to split LPS aggregates into monomeric molecules that are presented to the TLR4-MD2 complex. TLR4-MD2 complexes dimerize after binding LPS, leading to activation of multiple signaling components including NFκB with the subsequent production of pro-inflammatory cytokines in a MyD88-dependent signaling cascade1–3. Some of the TLR4-MD2 complexes become endocytosed and signal interferon regulatory factor 3 (IRF3) through a Trig-dependent signaling cascade leading to the production on Type I interferons (IFNa and IFNb). CD14 recognizes more than LPS however, as it has broad ligand specificity by recognizing structural motifs in various PAMPs and DAMPs, such as peptidoglycan, lipoteichoic acid, lipoarabinomannan and lipoproteins.4,5. As such, CD14 plays an important role by amplifying signals to other TLRs, such as TLR2 and TLRs 3, 6, 7, 8, and 96.

Figure 1. Mechanisms of membrane bound CD14 activity.

Figure 1.

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CD14 monomerizes lipopolysaccaride (LPS) aggregates extracted by the acute phase reactant LPS-binding protein (LBP). LBP transfers LPS to CD14, allowing CD14 to split LPS aggregates into monomeric molecules that are presented to the TLR4-MD2 complex. TLR4-MD2 complexes dimerize after binding LPS, leading to activation of MyD88 dependent activation of NFkB and subsequent production of pro-inflammatory cytokines. TLR4-MD2 complexes are also endocytosed and signal interferon regulatory factor 3 (IRF3) through a Trig-dependent signaling cascade leading to the production on type I interferons.

The distribution and regulation of CD14 has been studied in both murine and human models. In murine models CD14 mRNA has been detected in many tissues, including the kidney where it is produced by both immune and parenchymal cells and is upregulated by LPS7. In humans, CD14 protein has been detected in the cerebral cortex, lung, GI tract, testis, lymph nodes and kidneys. In the kidney, CD14 is primarily expressed in renal tubules, although low levels are also seen in glomeruli (Human Protein Atlas available from http://www.proteinatlas.org). CD14 is found in both membrane and soluble forms (mCD14 and sCD14). Membrane-bound CD14 facilitates activation of several extracellular and endosomal TLRs1, whereas soluble CD14 presents PAMPs and DAMPs to other cells, such as endothelial cells, resulting in cytokine production and expansion of proinflammatory responses2.

CD14 as a therapeutic target

CD14 was first recognized to be a potential therapeutic target when it was discovered to prevent synthesis of TNFa by lymphocytes stimulated with endotoxin in cell culture8. Subsequent ex vivo studies confirmed that sCD14 enhanced LPS stimulation of endothelial and epithelial cells9. Preclinical studies in primates confirmed that antibodies against CD14 could prevent endotoxin-induced shock10. Other preclinical studies in sepsis models laid the groundwork for the development of antibodies directed against CD14 to suppress inflammation11. Early studies showed anti-CD14 inhibited LPS-induced intracellular signaling and cytokine production in a lethal murine E. coli sepsis12. In a pig model of E. coli sepsis anti-porcine CD14 inhibited LPS-induced cytokine production13. In a subsequent pig study, CD14 inhibition blocked inflammatory cytokine responses, preserved leukocyte counts, reduced granulocyte enzyme matrix metalloproteinase-9 release and decreased expression of the granulocyte membrane activation molecule wCD11R3, the analog of CD11b in humans14. Based on these early findings, neutralization of CD14 was considered a promising treatment for sepsis14. Interestingly, organ specific effects of anti-CD14 antibody treatment were noted in the pig sepsis models15. Lungs, liver, spleen and kidneys examined for bacteria counts and inflammatory biomarkers showed IL6 was significantly inhibited in all organs while IL1b was inhibited only in the liver, spleen, and kidneys in the group that received the anti-CD14 treatment. The expression of TNF and IL8 however was inhibited only in the spleen, whereas ICAM-1 and VCAM-1 expression was significantly decreased in the kidneys. These studies suggested that anti-CD14 directed therapies might influence inflammatory responses in an organ-specific manner and set the stage for considering anti-CD14 therapy to prevent ischemic injury of donor organs procured for transplant15.

Organ-specific effects of CD14 blockade

Kidney

Several studies in experimental renal injury models have shown that CD14-dependent signals contribute to renal tubular damage and inflammation. In a unilateral ureteral obstruction model, CD14 was shown to be upregulated by TNFa in renal tubular epithelial cells; and notably the upregulation was not attributable to infiltration of the kidneys by mononuclear cells16. CD14 mRNA expression was also shown to be increased in the kidney following ischemia reperfusion injury (IRI) in a murine model where renal ischemia was induced by thoracic aortic occlusion17, In a rat model CD14 was found to be one of several genes expressed in association with renal IRI18. Using CD14 deficient mice it was shown that the absence of CD14 prevented biglycan-mediated cytokine expression, recruitment of macrophages, M1 macrophage polarization, renal tubular damage and dysfunction following renal IRI19. Another study in humans detected sCD14 in the urine of normal subjects. However, in the presence of sCD14 and LBP, proximal tubular cells were 10–100 fold more sensitive to LPS activation and sCD14 and LBP were required for proximal tubular necrosis induced by LPS20. While there are no published studies to date of anti-CD14 antibodies in experimental kidney transplant models, Kaczorowski showed that CD14 deletion might be important to ameliorate cold IRI of hearts21. The later study suggested that anti-CD14 directed therapies might be applied to organ preservation strategies in solid organ transplantation.

Liver

TLR4 is well-known to play an important role in liver IRI22,23. It is therefore no surprise that CD14 has also been found to play an important role in hepatic ischemia models. Tsoulfas demonstrated LBP and CD14 mRNA were significantly upregulated following reperfusion of donor livers preserved in cold UW solution and CD14 mRNA expression was correlated with length of cold ischemia time24. In a warm liver IR injury model, Cai noted upregulation of CD14 mRNA and increased soluble CD14 levels in the circulation after reperfusion and confirmed that CD14 knockout mice were protected from hepatic IRI25. In subsequent studies, Luan demonstrated that CD14 and TLR4 mRNA and protein expression were significantly upregulated in Kupffer cells by hepatic IRI26 and that anti-CD14 antibody treatment significantly decreased NFkB and TNFa activity in Kupffer cells after warm IRI26. Cai showed that CD14 mRNA and sCD14 were increased by warm ischemia25. CD14 knockout mice had lower IL6 levels and less severe liver necrosis after IRI, and pretreatment with anti-CD14 antibody (before the ischemic injury) was more protective than administration of anti-CD14 before reperfusion as measured by liver injury and inflammatory responses25.

Heart

The role of TLR4 in cardiac IRI has been well documented, and it is reasonable that CD14 might be a potential target for ischemic cardiac injury as well. The results of multiple studies reveal that myocardial inflammation and ischemic injury is reduced in the absence of TLR4 signaling27–31. Using a model of left anterior descending (LAD) artery occlusion in TLR deficient mice, several investigators have observed reduced myocardial infarct size and lower levels of proinflammatory cytokines in mice that lack functional TLR4 signaling29,32, suggesting that TLR4 signaling contributes to myocardial injury and inflammation after warm IRI. In evaluating the clinical potential of TLR4 inhibition as a target for myocardial warm IRI, Shimamoto and co-investigators treated mice with Eritoran, a soluble analog of lipid A that serves as an inhibitor of TLR4 and found significantly reduced infarct size, decreased JNK phosphorylation and decreased NFκB nuclear translocation in hearts of treated animals that were pre-treated with Eritoran33. TLR4 is expressed on multiple different donor and recipient cell types including leukocytes, endothelial cells, dendritic cells, and cardiomyocytes and data in heterotopic heart transplants further suggested that TLR4 signaling on both graft and recipient cells contributed to systemic and intragraft inflammatory responses in the setting of cold IRI and cardiac transplantation21,34.

Substantial evidence from the literature demonstrates cardiac myocytes express CD14 and that blocking CD14, either with an anti-CD14 antibody or by genetic deletion of CD14, can abrogate tissue injury. In a model of LPS stimulated chick embryo cardiomyocytes, CD14 expression was found to be expressed on the surface membranes of cardiomyocytes35. Kaczorowski showed that CD14 deficient syngeneic murine donor hearts subjected to 2 hr of cold ischemia and 3 hr of reperfusion had lower post-transplant IL6 and MCP-1 levels after cold IRI in comparison to the wild-type hearts and that intragraft TNFa and IL1b mRNA levels were also significantly lower in CD14 KO grafts30.

In humans, CD14 expression has been associated with ischemic heart disease. In patients with congestive heart failure (CHF), an antibody to CD14 (IC14) suppressed LPS-stimulated whole blood TNF production in patients with CHF and therefore was considered to be a potential novel therapeutic strategy for CHF patients with systemic immune activation36. CD14 gene polymorphisms have also been reported to be associated with ischemic heart disease, however a large meta-analyses only found an association with ischemic heart disease to be in a select East Asian patient population, and more studies to detect associations were recommended37.

Lung

Lung transplantation is routinely challenged by innate immune activation events that limit the ability to use donor lungs. High rates of bacterial contamination are common, due to prolonged mechanical ventilation of the deceased donor, aspiration of gastric contents around the time of death and immune dysfunction after brain death. As a result, donor lung utilization rates are the lowest among all solid organs (www.unos.org). The presence of bacteria in donor lungs is associated with increased risk for donor IRI and primary graft dysfunction (PGD)38. One of the key mechanisms triggered by transplant related IRI in the lungs is activation of intravascular monocytes by DAMPs that persist in the donor lungs despite pathogen clearance39. Using RNAseq analyses of donor resident alveolar macrophages, Akbarpour found that TLR4 and CD14 were significantly upregulated in donor lungs after IRI40. Then using a TLR4 antagonist (TAK-242) or CD14/TLR4 antagonist (IAXO-101) this group transplanted donor lungs into WT recipients and found that anti-TLR4 treatment suppressed neutrophil influx after transplantation, and that this upregulation was associated with levels of LPS insufficient to induce detectable injury before transplantation40. The authors suggested that strategies blocking TLR4 or coreceptor CD14 in the donor organ might reduce neutrophil recruitment and PGD in donor lungs procured for transplantation40. In patients with acute lung injury (manifest as ARDS), lung lavage fluids have been found to contain high concentrations of sCD1441 and antibody blocking of CD14 reduced neutrophil concentrations in bronchoalveolar lavage (BAL) fluid and cytokine concentrations in BAL fluid and plasma in a pilot study41.

CD14 and clinical relevance to transplantation

The potential therapeutic relevance of CD14 in ischemia reperfusion injury has been well-documented by preclinical studies in animal and human models (Table 1)42. Targeting CD14 provides a way to inhibit multiple proximal innate immune activation events associated with ischemia of the donor organ. Antibodies against CD14 have been shown in animal models to block ischemic tissue injury and human trials of anti-CD14 monoclonal antibodies in sepsis are ongoing43. All organs recovered for transplantation undergo IRI and applying a therapy that targets a proximal point in innate immune activation is an approach that might improve viability of deceased donor organs and greatly increase organ availability.

Table 1.

Organ specific studies that suggest CD14 as a target for organ specific IRI

Kidney

  • CD14 upregulated on renal tubule cells after unilateral ureteral obstruction16

  • CD14 expression increased in kidney after thoracic aortic occlusion17

  • CD14 expression increased in kidney after warm ischemia/reperfusion18

  • CD14 knockout mice protected from renal ischemia/reperfusion injury19

  • sCD14 and LBP induce human proximal tubule necrosis in vitro20
Liver

  • LBP and CD14 mRNA increase in liver after cold ischemia/reperfusion injury24

  • CD14 mRNA and sCD14 levels increase after warm liver ischemia/reperfusion injury25

  • CD14 and TLR4mRNA upregulated on Kupffer cells by ischemia/reperfusion injury26

  • CD14 mRNA and sCD14 increased by warm liver ischemia/reperfusion injury25
Heart

  • Myocardial inflammation/ischemic injury reduced in absence of TLR4 signaling27,28,30,31

  • Reduced myocardial infarct size in the absence of TLR4 29,32

  • Pretreatment with Eritoran protected from cardiac ischemia/reperfusion injury33

  • Cardiac myocytes express CD14 and blocking CD14 protects from cardiac injury35

  • CD14-deficient hearts protected from cardiac ischemia/reperfusion injury30

  • CD14 expression in human hearts associated with ischemic heart disease36
Lung

  • TLR4 and CD14 upregulated in donor lungs after ischemia/reperfusion injury39

  • CD14/TLR4 antagonists suppressed neutrophil influx after lung ischemia/reperfusion injury40

  • Patents with ARDS have high concentrations of sCD14 in lung lavage fluids41
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A number recently published studies suggest that targeting CD14 might also provide a new therapeutic strategy to down regulate immune responses after transplantation44. CD14 has been proposed to function as an apoptotic cell receptor on monocytes45,46 and has also been shown to bind to T cells and convey a negative signal inhibiting interleukin 2 (IL2), IL4 and gamma interferon by inactivating NFkB47–49. Thus, targeting CD14 in the post-transplant period might provide a novel approach to immunosuppression and certainly further studies will help provide insights into the effects of CD14 on T cell anergy and possibly tolerance induction.

Highlights:

  • CD14 is an accessory protein that greatly increases cellular responses to PAMPs and DAMPs

  • CD14 has been recognized for over three decades to play an essential role in innate immune signals associated with sepsis

  • Genetic deletion or antibody blockade of CD14 has been shown to modify ischemic tissue injury in the kidney, liver, heart and lung

  • Multiple experimental animal studies and observations in human organs suggest CD14 blockade as a therapeutic target to ameliorate donor organ injury

Acknowledgements:

This work was supported by grants from the national Institutes of Health awarded to DM (R01DK113162, RO1DK128547 and R21AI5433471).

Abbreviations:

CD14

cluster of differentiation 14

MD2

myeloid-differentiation factor 2

PRR

pattern recognition receptor

TLR

toll-like receptor

NLR

nucleotide-binding oligomerization domain-like receptor

PAMP

pathogen-associated molecular pattern

DAMP

damage-associated molecular pattern

IRI

ischemia reperfusion injury

LPS

lipopolysaccharide

LBP

LPS binding protein

Footnotes

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Declarations of interest: none

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