# Apoptosis inhibitor of macrophage

Apoptosis inhibitor of macrophage (AIM) is a protein produced by macrophages that regulates immune responses and inflammation. It plays a crucial role in key intracellular processes like lipid metabolism and apoptosis.

## Overview

AIM, a 40 kDa protein encoded by the CD5L gene, is predominantly produced by tissue-resident macrophages through transcriptional activation of nuclear receptors (LXR/RXR) and/or transcription factor MAFB. Belonging to the scavenger receptor cysteine-rich (SRCR) superfamily, AIM has three SRCR domains. In serum, AIM binds to IgM pentamers, preventing renal excretion and maintaining high circulating levels. While AIM bound to IgM is inactive, it dissociates during diseases for its functional role in promoting disease repair. The specific binding mode of AIM to the IgM-Fc pentamer remains unclear. AIM-Fc binding is comparable to antibody-antigen interaction, with low affinity. GSK3 regulates AIM expression through activated STAT3, affecting the AIM promoter activity.
A study published in 2019 found that AIM exhibited a broader expression pattern in dogs than previously observed in humans and mice. The study on mature healthy Beagles revealed AIM expression in tissue macrophages of the spleen, liver, lungs, lymph nodes, and proximal tubules in the kidney. AIM was also found in circulating monocytes, B lymphocytes, and specific microvasculature endothelial cells. Early-stage monocyte progenitor-like cells in the bone marrow also expressed AIM.

## Functions

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.
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.
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.

### 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.

### 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.

### 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.
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.

### 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.
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.

### Effect of AIM in different diseases

| Type of diseases | Main functions |
| Lipid metabolism | AIM influences macrophage homeostasis, survival, adhesion to endothelial cells, oxidized LDL uptake, and foam cell formation. |
| 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. |