Allograft inflammatory factor 1 (AIF-1) also known as ionized calcium-binding adapter molecule 1 (IBA1) is a protein that in humans is encoded by the AIF1 gene. [5] [6]
Allograft inflammatory factor 1 (AIF-1) also known as ionized calcium-binding adapter molecule 1 (IBA1) is a protein that in humans is encoded by the AIF1 gene. [5] [6]
The AIF1 gene is located within a segment of the major histocompatibility complex class III region. It has been shown that this gene is highly expressed in testis, spleen, and brain but weakly expressed in lung, and kidney. Among brain cells, the Iba1 gene is strongly and specifically expressed in microglia. Circulating macrophages also express Iba1.[ citation needed ]
AIF1 is a protein that exists in the cytoplasm, and it is highly evolutionarily conserved. It is also possibly identical to three other proteins, Iba-2, MRF-1 (microglia response factor) and daintain. However complete functional profiles of all three proteins and how they overlap is unknown. [7] IBA1 is a 17-kDa EF hand protein that is specifically expressed in macrophages / microglia and is upregulated during the activation of these cells. Iba1 expression is up-regulated in microglia following nerve injury, [8] central nervous system ischemia, and several other brain diseases.
AIF1 was originally discovered in atherosclerotic lesions in a rat model of chronic allograft cardiac rejection. It was found to be upregulated in macrophages and neutrophils in response to the cytokine IFN-γ. [9] AIF1 expression has been seen to increase in vascular tissue in response to arterial injury, specifically it is found in activated vascular smooth muscle cells in response to IFN-γ, IL-1β, and T-cell conditioned media. [10] In vascular smooth muscle cells, activation is responsible for arterial thickening in allografts through over proliferation. AIF1 has been found to enhance growth and promote proliferation in vascular smooth muscle cells through deregulation of the cell cycle. It does this by shortening the cell cycle and altering the expression of cyclins. [11] Though histologically different, AIF1 has also been shown to promote the proliferation and activation of endothelial cells (EC). EC activation, leads to proliferation and migration of cells, which is involved in multiple normal vascular processes, such as atherosclerosis, angiogenesis, and wound healing. It is currently theorized that AIF1 works to control endothelial cell proliferation and migration through action in signal transduction pathways. [12] It has features of a cytoplasmic signaling protein, including several domains that allow for binding to multiprotein complexes, called PDZ domains. [13] In endothelial cells, AIF1 has been specifically shown to regulate vasculogenesis, including the formation of aortic sprouting and tube-like formations. AIF1 been shown to interact with kinase p44/42 and PAK1, two previously known signal transduction molecules, in regulating these processes. AIF1 also shows distinct differences in the pathways by which it regulates endothelial cells, macrophages, and vascular smooth muscle cells. [12] Upregulation of AIF-1 is connected with increased migration of mononuclear peripheral blood cell. In the CD14 positive cells, AIF-1 support secretion of IL-6 and various chemokines. [14] AIF-1 may also play a role in the T-cell response. It has been shown that AIF-1 increases expression of IL-2 and IFN-γ in T-cells, while the expression of IL-4 and TGF-β is decreased. The presence of AIF-1 also inhibits polarization into regulatory T cells. [15]
Allograft Inflammatory Factor 1 is found in activated macrophages. Activated macrophages are found in tissues with inflammation. AIF1 levels in healthy humans have been found to positively correlate with metabolic indicators, such as body mass index, triglycerides, and fasting plasma glucose levels. The excess of adipose tissue found in obese patients is found to cause chronic inflammation with an increase in the number of activated macrophages. Subsequently, AIF1 may be an accurate indicator of macrophage activation in the body. [16] There is also evidence that AIF1 could be a marker for diabetic nephropathy when detected in serum. [17] Since diabetic nephropathy is a consequence of long-term type 1 and type 2 diabetes, this consistent with evidence that AIF1 may be associated with other aspects of diabetes. It is found in activated macrophages in the pancreatic islets, and has been shown to decrease insulin secretion, while simultaneously impairing glucose elimination. [18]
In recent years, the possibility of a role for AIF-1 in cancer development has also been considered. Significantly higher levels of AIF-1 expression were found in hepatocarcinoma cell lines and in tissue compared to healthy samples. One option in which AIF-1 may contribute to the development of pathology is involvement in the proliferation and migration of tumor cells. [19] It was also shown that AIF-1 promote cell proliferation in the brest cancer cells line. This effect was dependent on time and level of AIF-1 protein. [20] Upregulation of AIF-1 enhanced activity of NF-ΚB and increased expression of cyclin D1. Cyclin D1 contribute to cell proliferation and mutation in this gene has been connected with variety of tumors. It has also been shown that AIF-1 expression can contribute to progression of cancer by inhibition of apoptosis in cells. [21] [22]
The role of up-regulation of expression of AIF-1 was demonstrated in rheumatoid arthritis. Presence of AIF-1 was confirmed in synovial tissue of patient with this pathology. AIF-1 was strongly expressed in several cell types of synovial tissue, such as fibroblast and synovial cells, but also in infiltrated immune cells. It was also shown that upregulation of AIF-1 contribute to induction of enhances the production of IL-6 . Another factor by which the expression of AIF-1 affects the course of the disease is increased proliferation of synovial cells. [23]
AIF-1 was also considered as a player in the diseases connected with fibrosis. For example, in kidney diseases overexpression of AIF-1 in the macrophages contributes to signaling through AKT and mTOR. Another way in which AIF-1 contribute to the pathology of kidney is upregulation of enzyme NADPH oxidase 2. This upregulation leads to oxidative stress in the cells and progression of renal injury. [24] Expression of AIF-1 is considered to be linked with calcification in hemodyalisis patients. Higher presence of AIF-1/NF-κB/MCP-1/CCR-2-pathway was detected in calcifaied vascular smooth muscle cells. AIF-1 was also detected as a potential factor which contribue to apoptosis and inflammation. [25]
Since the immune response in the retina is tightly regulated under physiological conditions, microglia may play a role in retinal diseases. [26] Retinitis pigmentosa is an inherited disease in which photoreceptors are gradually degenerated. That condition gradually leads to reduced of dark vision and eventually complete blindness. In an experimental model RCS (The Royal College of Surgeons) rats with progression loss of photoreceptors, level of AIF-1 was elevated in retina in contrast to wild type [27]
Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.
Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia originate in the yolk sac under a tightly regulated molecular process. These cells are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.
Macrophage Inflammatory Proteins (MIP) belong to the family of chemotactic cytokines known as chemokines. In humans, there are two major forms, MIP-1α and MIP-1β that are now officially named CCL3 and CCL4, respectively. However, other names can sometimes be encountered, especially in older literature, as LD78α, AT 464.1 and GOS19-1 for human CCL3 and AT 744, Act-2, LAG-1, HC21 and G-26 for human CCL4. Other macrophage inflammatory proteins include MIP-2, MIP-3 and MIP-5.
Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.
Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.
OX40L is the ligand for OX40 and is stably expressed on many antigen-presenting cells such as DC2s, macrophages, and activated B lymphocytes.
CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.
Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A (CypA) or rotamase A is an enzyme that in humans is encoded by the PPIA gene on chromosome 7. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate many biological processes, including intracellular signaling, transcription, inflammation, and apoptosis. Due to its various functions, PPIA has been implicated in a broad range of inflammatory diseases, including atherosclerosis and arthritis, and viral infections.
Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
Probable G-protein coupled receptor 84 is a protein that in humans is encoded by the GPR84 gene.
Prostaglandin E2 receptor 2, also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.
Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.
Tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein or TSG-6 is a protein that in humans is encoded by the TNFAIP6 gene.
The S100 calcium-binding protein mS100a7a15 is the murine ortholog of human S100A7 (Psoriasin) and human S100A15 (Koebnerisin). mS100a7a15 is also known as S100a15, mS100a7 and mS100a7a and is encoded by the mS100a7a gene
Calponin 2 is a protein that in humans is encoded by the CNN2 gene.
Immune system contribution to regeneration of tissues generally involves specific cellular components, transcription of a wide variety of genes, morphogenesis, epithelia renewal and proliferation of damaged cell types. However, current knowledge reveals more and more studies about immune system influence that cannot be omitted. As the immune system exhibits inhibitory or inflammatory functions during regeneration, the therapies are focused on either stopping these processes or control the immune cells setting in a regenerative way, suggesting that interplay between damaged tissue and immune system response must be well-balanced. Recent studies provide evidence that immune components are required not only after body injury but also in homeostasis or senescent cells replacement.
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