CD5L

CD5 antigen-like is a protein (also known as AIM, for apoptosis inhibitor of macrophage) that in humans is encoded by the CD5L gene.^[5][6] It is expressed by macrophages. It regulates immune responses and inflammation. It plays a crucial role in key intracellular processes like lipid metabolism and apoptosis.

CD5L
Identifiers
Aliases	CD5L, AIM, API6, PRO229, SP-ALPHA, Spalpha, CT-2, hAIM, CD5 molecule like
External IDs	OMIM: 602592; MGI: 1334419; HomoloGene: 55936; GeneCards: CD5L; OMA:CD5L - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q23.1 Start 157,830,911 bp[1] End 157,898,256 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 F1 Start 87,265,188 bp[2] End 87,278,380 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in spleen trabecular bone liver testicle right lobe of liver buccal mucosa cell lymph node bone marrow bone marrow cell placenta Top expressed in stroma of bone marrow fetal liver hematopoietic progenitor cell mesenteric lymph nodes left lobe of liver spleen calvaria tibiofemoral joint granulocyte human fetus subcutaneous adipose tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function scavenger receptor activity Cellular component cytoplasm extracellular region extracellular exosome blood microparticle membrane extracellular space plasma membrane cell surface Biological process cellular defense response inflammatory response receptor-mediated endocytosis immune system process apoptotic process vesicle-mediated transport regulation of complement activation positive regulation of complement-dependent cytotoxicity endocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 922 11801 Ensembl ENSG00000073754 ENSMUSG00000015854 UniProt O43866 Q9QWK4 RefSeq (mRNA) NM_005894 NM_001347698 NM_009690 RefSeq (protein) NP_001334627 NP_005885 NP_033820 Location (UCSC) Chr 1: 157.83 – 157.9 Mb Chr 3: 87.27 – 87.28 Mb PubMed search [3] [4]
Wikidata
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Gene

AIM, also known as apoptosis inhibitor of macrophage, is a 40 kDa protein encoded by the CD5L gene. Its expression is predominantly driven by tissue-resident macrophages via transcriptional activation of nuclear receptors such as LXR and RXR, and/or the transcription factor MAFB. Expression is further regulated by GSK3 through activation of STAT3, which influences CD5L promoter activity.^[7]

Structure

AIM belongs to the scavenger receptor cysteine-rich (SRCR) superfamily and contains three SRCR domains. In serum, AIM forms complexes with IgM pentamers, which prevents its renal excretion and enables sustained high circulating levels. While the IgM-bound form is functionally inactive, AIM dissociates under pathological conditions to perform biological functions involved in disease resolution. The binding between AIM and IgM-Fc is of low affinity and resembles an antibody–antigen interaction, although the precise molecular binding mode remains unclear.^[7]

Tissue distribution

A 2019 study reported that AIM is more widely expressed in dogs than previously described in humans and mice. In healthy adult Beagles, AIM was detected in tissue macrophages of the spleen, liver, lungs, lymph nodes, and proximal tubules of the kidney. Expression was also found in circulating monocytes, B lymphocytes, and certain microvascular endothelial cells. Additionally, early-stage monocyte progenitor-like cells in the bone marrow expressed AIM.^[8]

Function

AIM plays a pleiotropic role in the body. Its diverse functions include regulating intracellular processes such as lipid metabolism and apoptosis, inhibiting cholesterol synthesis, and influencing Th17 cell pathogenicity. Despite its diverse impact on inflammatory regulation, studies have yet to uncover the mechanisms determining its varying roles— beneficial or harmful. The specific receptor for AIM is unclear, but it can bind to molecules like CD36, a membrane glycoprotein involved in various cellular functions, including inflammation and atherosclerosis. Inflammatory responses act as a "double-edged sword", underscoring the importance of maintaining balance for effective host defense while minimizing adverse side effects associated with acute inflammation.^[7]

Clinical significance

AIM has been found to increase in autoimmune diseases, directly targeting liver cells in liver cancer and promoting cell clearance in acute kidney injury. It has also been found to contribute to arteriosclerosis and cardiovascular events, and to aggravate inflammatory reactions in lung diseases and sepsis.^[7]

In autoimmune diseases

Elevated AIM expression in autoimmune diseases serves as a potential biomarker, yet its role and mechanism remain unclear. In ALS, secondary progressive multiple sclerosis, rheumatoid arthritis, and osteoarthritis, AIM levels are elevated, making it a sensitive biomarker for disease activity. In knee-OA patients, AIM in CD14+ macrophages suggests a potential role in enhancing synovial macrophage survival and promoting arthritis. In lupus, AIM concentration correlates with disease activity and inflammatory markers, decreasing after effective treatment. In psoriasis, AIM may contribute to the inflammatory environment by inhibiting macrophage apoptosis. In Crohn's disease, AIM secretion by active macrophages causes intestinal inflammation, aiding in distinguishing it from other intestinal diseases. Though AIM levels in Crohn's disease show no correlation with disease activity or clinical characteristics, the increment of AIM may contribute to its pathogenesis by inhibiting macrophage apoptosis and sustaining inflammation.^[7]

In cardiopulmonary diseases

The role of AIM in cardiovascular and pulmonary diseases centers around inflammation, inhibiting macrophage apoptosis, and enhancing inflammatory responses. In cardiovascular disease, AIM exacerbates metabolic disorders and atherosclerosis, contributing to diabetes mellitus and cardiovascular events. AIM is highly expressed in foam macrophages within atherosclerotic plaques, promoting macrophage survival and inflammatory responses. AIM deficiency in mice shows improved outcomes after myocardial infarction, including increased survival, reduced heart rupture, and altered macrophage profiles. In pulmonary diseases, AIM serves as a valuable biomarker for differentiating bacterial from viral infections and predicting mortality in pneumonia. In lung injury scenarios, AIM influences inflammatory signals and bacterial clearance.^[7]

Dual role in liver inflammatory damage

AIM plays a dual role in liver dynamics. In lipid metabolism, it contributes to lipolysis-related inflammation, while in the liver's microenvironment, it counters TGFβ1's pro-fibrotic effects during liver disease. This adaptive response aims to mitigate inflammatory signaling and fibrosis. In liver injury models, AIM exhibits a protective role against fibrosis, influencing injury prevention, immune cell infiltration, and a shift in macrophage phenotypes. However, while AIM from Kupffer macrophages triggers complement-dependent cytotoxicity, inducing tumor cell death, its heightened expression in hepatocellular carcinoma (HCC) is linked to aggressive tumor characteristics, enhanced proliferation, and resistance to apoptosis.^[7]

AIM's distinct origins, whether from the bloodstream or hepatic macrophages, contribute differently to liver health. Circulating AIM inhibits obesity and fatty liver disease, while non-circulating AIM from macrophages impedes HCC development by directly targeting cancerous liver cells. The interaction with scavenger receptors further refines AIM's impact, triggering complement-dependent cytotoxicity most effectively in the liver. In drug-induced liver injury, AIM's increased expression contributes to mitochondrial oxidative stress, and the loss of circulating AIM in acute and chronic liver failure correlates with multiple organ failures, highlighting its broader implications in systemic inflammation.^[7]

Dual role in kidney function

In serum, AIM, released from the IgM pentamer, serves diverse purposes, including its involvement in acute kidney injury (AKI) . A 2016 study published in Nature Medicine highlighted the role of apoptosis inhibitor of macrophage in promoting recovery from AKI in mice. AIM, increased during AKI, binds to kidney injury molecule (KIM)-1, facilitating the clearance of cellular debris in the kidney and aiding tissue repair. AIM-deficient mice with AKI displayed impaired debris clearance and increased mortality. Treating AKI mice with recombinant AIM improved renal pathology, offering a potential basis for novel AKI therapies.^[9]

In nephropathies, AIM demonstrates a dual role with complex consequences. In IgA nephropathy (IgAN) models, recombinant AIM restores glomerular IgM/IgG co-deposition, suggesting its involvement in kidney damage. In IgAN patients, urinary AIM levels correlate with renal inflammation indicators, emphasizing its multifaceted role. AIM, originating from infiltrating macrophages, becomes an additional source of urinary AIM, challenging the perception that serum-free AIM is the sole contributor.^[7]

Obesity

Research conducted by researchers at the University of Tokyo in 2011 revealed that AIM increases in blood with obesity progression, promoting lipolysis in adipose tissue. This response is crucial for recruiting adipose tissue macrophages, facilitated by AIM-induced chemokine production through toll-like receptor 4 (TLR4) activation. Administering recombinant AIM to TLR4-deficient mice induces lipolysis without chemokine production, preventing inflammatory macrophage infiltration into adipose tissue and mitigating obesity-related inflammation, insulin resistance, and glucose intolerance. These findings suggest that targeting AIM could be a therapeutic approach for preventing obesity-related metabolic disorders.^[10]

Effect of AIM in different diseases

Type of diseases	Main functions	Source
Lipid metabolism	AIM influences macrophage homeostasis, survival, adhesion to endothelial cells, oxidized LDL uptake, and foam cell formation.	[7]
Hepatic disease	AIM plays a protective role against fibrosis, preventing injury, fibrosis, immune cell infiltration, and altering macrophage phenotype.
Hepatocellular carcinoma (HCC)	AIM deficiency in mice leads to increased HCC tumors, and elevated AIM levels in liver tumors are associated with aggressive tumor characteristics.
Renal disease	AIM accumulation on dead cell debris in the kidneys promotes phagocytosis and clearance, contributing to renal tissue repair.
Cardiovascular disease	AIM initiates obesity-related chronic inflammation, leading to insulin resistance, atherosclerosis, and cardiovascular events.
Pulmonary disease	Serum AIM aids in differentiating bacterial from viral infections, predicts mortality in pneumonia, and influences macrophage and neutrophil responses.
Autoimmune disease	Elevated AIM levels are found in various autoimmune diseases, acting as a sensitive biomarker for disease activity.
Tuberculosis	AIM enhances macrophage killing activity in response to tuberculosis infection.
Peritonitis	AIM deficiency leads to persistent peritoneal inflammation, affecting pro-inflammatory cytokine release and mesenchymal cell redistribution.
Sepsis	AIM down-regulates inflammatory cytokines in sepsis, disrupting immune homeostasis and inducing abnormal IL-10 production.
Chronic kidney disease	AIM dissociation from pentameric IgM is positively correlated with prognosis after hemodialysis initiation.[11]

Veterinary medicine

Cat

See also: Chronic kidney disease in cats

A 2016 study attributed the high susceptibility of house cats to kidney disease to the inability of feline AIM protein to enter the urine. In cats—including domestic cats, lions, and tigers—AIM is very tightly bound to IgM pentamers in the bloodstream. This prevents its passage into the nephrons and impairs the clearance of dead cells following renal injury. In contrast, AIM in humans and mice dissociates from IgM under pathological conditions, enabling tissue repair. Mice genetically engineered to express feline AIM in place of their native CD5L exhibited increased mortality following acute kidney injury.^[12][13] Similar patterns have been reported in human patients with chronic kidney disease.^[11]

Two genotypes of feline AIM have been identified. The common variant encodes three SRCR domains, similar to other mammals, while a less frequent allele encodes four SRCR domains due to a duplication. Although this variant binds IgM with reduced affinity, it still fails to dissociate following kidney injury.^[13]

A 2015 patent described the use of recombinant feline and murine AIM administered by injection in cats as an experimental treatment for kidney injury.^[14]

Therapeutic strategies based on AIM, including injectable AIM and small molecules that promote its release from IgM, have been proposed for use in both cats and humans.^[15] In 2022, a commercial cat supplement branded as "AIM30" was released, claiming to enhance AIM activity via a proprietary "A-30" amino acid, reportedly developed with input from researchers involved in AIM studies.^[16] However, there is no evidence supporting the existence of such an amino acid in the scientific literature or among the product’s listed ingredients. Unverified claims of AIM injections undergoing clinical trials in cats also circulated in 2024.^[17]