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CCL3

CCL3, also known as macrophage inflammatory protein 1-alpha (MIP-1α), is a small inducible belonging to the CC chemokine family that functions primarily as a chemoattractant for immune cells during inflammatory responses. Encoded by the CCL3 gene on human chromosome 17q12, it is produced mainly by activated s, monocytes, T cells, and dendritic cells, and plays a key role in orchestrating leukocyte recruitment to sites of or tissue damage. The protein is synthesized as a 92-amino-acid precursor that undergoes to yield a mature form of 69 , featuring a conserved fold with an N-terminal disordered region, a three-stranded antiparallel β-sheet, and a C-terminal α-helix connected by two bridges (Cys11–Cys36 and Cys12–Cys52). CCL3 tends to oligomerize into dimers via N-terminal β-sheet interactions and can form higher-order rod-like polymers exceeding 600 , which enhance its resistance to but reduce monomeric receptor-binding efficiency. Expression is upregulated in response to proinflammatory stimuli like , interleukin-1β, or , with highest basal levels observed in and liver tissues. CCL3 mediates its biological effects by binding to G protein-coupled receptors CCR1 and (with lower affinity for CCR3 and ), activating pathways such as PI3K/Akt and MAPK that drive , calcium mobilization, and cell activation in target leukocytes. Key functions include attracting monocytes, T lymphocytes, natural killer cells, and to inflammatory sites; inhibiting hematopoietic proliferation; and promoting osteoclast differentiation and via enhancement. It also contributes to antiviral immunity by suppressing HIV-1 replication in CD8+ T cells and inhibiting progenitors to prevent viral spread. In disease contexts, CCL3 is implicated in chronic inflammation and pathology, with elevated levels correlating to tissue damage in (where it drives synovial infiltration and joint erosion), (promoting lytic bone lesions), and other conditions like periodontitis, , and certain cancers. Genetic variations in CCL3, such as promoter polymorphisms, influence susceptibility to HIV-1 infection and inflammatory disorders like . Due to its role in immune modulation, CCL3 has emerged as a potential for disease monitoring and a target for therapeutic interventions in inflammatory and neoplastic diseases.

Molecular Biology

Gene

The CCL3 is located on the long arm of human chromosome 17 at position 17q12, specifically spanning genomic coordinates 36,088,256–36,090,169 on the reverse strand. In mice, the orthologous resides on at coordinates 83,538,670–83,540,181. This positioning places CCL3 within a cluster of CC genes on chromosome 17q12, reflecting the genomic organization of the chemokine family. The CCL3 spans approximately 1.9 kb and consists of three exons separated by two introns, encoding a precursor protein of 92 that undergoes post-translational processing. The produces three transcripts, with the one encoding the 92-aa precursor. This compact structure is typical of small genes, facilitating rapid transcriptional responses. The encoded precursor serves as the basis for the mature CCL3 protein, detailed further in the protein structure section. Transcriptional regulation of CCL3 is primarily controlled by promoter elements responsive to nuclear factor kappa B () and activator protein 1 (AP-1), which drive inducible expression in immune cells such as macrophages and T cells. Cytokines including alpha (TNF-α) and interleukin-1 beta (IL-1β) activate these pathways, enhancing CCL3 transcription via MAPK, , and C/EBPβ signaling cascades. This regulation allows for swift upregulation in response to inflammatory stimuli, underscoring the gene's role in acute immune activation. Genetic variations in CCL3 include common single nucleotide polymorphisms (SNPs) such as rs5029410 in the 3' , which can influence mRNA stability and lead to altered expression levels. Other SNPs, like rs34171309 in exon 3, have been identified and may modulate transcriptional efficiency without directly impacting the protein coding sequence. These variants contribute to inter-individual differences in CCL3 expression, though their functional impacts require further context-specific analysis. The CCL3 gene exhibits strong evolutionary conservation across mammals, with orthologs identified in over 130 species including , , and , reflecting purifying selection to maintain functionality. This conservation highlights the gene's ancient origin within the CC family, predating primate-specific duplications.

The CCL3 protein is synthesized as a 92-amino acid precursor that undergoes post-translational processing to yield a mature 70-amino acid polypeptide with a molecular weight of approximately 7.8 kDa. The N-terminal (residues 1–23) is cleaved to produce the active form, which begins with serine at position 1 of the mature sequence. This compact structure is typical of CC chemokines and enables CCL3 to function as a potent inflammatory . Structurally, CCL3 exhibits the canonical fold, featuring a conserved where the first two residues (Cys12 and Cys13 in mature numbering) are adjacent and participate in two intramolecular bonds (Cys12–Cys36 and Cys13–Cys52) that stabilize the protein core. The overall architecture includes an N-terminal , a short 3₁₀ , a three-stranded antiparallel β-sheet (strands spanning residues ~25–56), and a C-terminal α- (residues ~57–70). In solution, CCL3 predominantly exists as monomers but can oligomerize into dimers via N-terminal β-sheet interactions and further into tetramers or higher-order polymers, which modulate its activity and presentation on cell surfaces or glycosaminoglycans. Post-translational modifications of CCL3 include , which adds heterogeneous carbohydrate moieties and increases the apparent molecular weight to 10–25 in some forms, thereby enhancing stability, solubility, and resistance to while influencing bioactivity. The of monomeric CCL3, determined at 1.76 in with a binding protein (PDB: 3FPU), underscores the flexible, basic N-terminal region (rich in positively charged residues) that is crucial for initial receptor engagement, with the core β-sheet and providing rigidity. Compared to other CC chemokines, CCL3 shares about 70% sequence identity with (also known as MIP-1β), particularly in the conserved framework and β-sheet regions, which underpin their overlapping yet distinct roles in immune responses.

Biological Functions

Immune Cell Recruitment

CCL3, also known as macrophage inflammatory protein-1α (MIP-1α), serves as a potent chemoattractant for multiple immune cell types by generating concentration gradients that direct their migration to inflammatory sites. It primarily attracts monocytes and macrophages, which express high levels of its receptors CCR1 and , facilitating their recruitment during early inflammatory responses. Additionally, CCL3 preferentially draws in activated CD8+ T cells and type 1 helper T cells (Th1), as well as and , thereby orchestrating a coordinated influx of adaptive and innate immune effectors. Beyond migration, CCL3 activates target cells through receptor-mediated signaling, inducing rapid intracellular calcium mobilization that triggers downstream effector functions. This leads to upregulation of such as (lymphocyte function-associated antigen 1), enhancing to and components. In and , CCL3 further promotes , releasing , leukotrienes, and other mediators that amplify local . These activation effects are dose-dependent, with optimal occurring at concentrations of 1-10 nM; higher doses, such as those exceeding 100 nM, result in receptor desensitization and diminished responsiveness. In vivo studies underscore CCL3's critical role in immune cell recruitment during bacterial infections. For instance, in models of LPS-induced , CCL3 drives influx by sequentially stimulating TNF-α and LTB4 release, leading to enhanced peritoneal accumulation and bacterial clearance. CCL3 also exhibits with other , such as (RANTES), to enhance T cell arrest on , promoting more efficient transendothelial migration in inflammatory contexts.

Inflammatory and Hematopoietic Roles

CCL3 exerts pro-inflammatory effects by inducing fever through prostaglandin-independent mechanisms involving CRF release in the brain. This pyrogenic activity is distinct from classical prostaglandin-mediated fevers and contributes to the acute phase response during infection. Additionally, CCL3 synergizes with cytokines such as IL-1 and TNF-α to amplify inflammatory cascades, enhancing the production of other pro-inflammatory mediators and participating in cytokine storms observed in severe infections like COVID-19, where elevated levels of CCL3 correlate with TNF-α and IL-1β. In hematopoietic functions, CCL3 promotes myeloid lineage from hematopoietic stem and cells (HSPCs), expanding the myeloid cell pool independently of stromal support. Conversely, it inhibits erythroid , particularly in contexts like , by activating CCR1 signaling that downregulates expression via p38 MAPK. Tissue-specific expression of CCL3 is upregulated in inflamed tissues, such as the lungs during models, where microbial stimuli like (LPS) from induce its production in epithelial and immune cells, exacerbating local . In animal models, CCL3 mice exhibit reduced in , with decreased joint swelling and synovial infiltration due to impaired recruitment of inflammatory monocytes, though this comes at the cost of impaired viral clearance, as evidenced by higher viral titers and delayed resolution of infections like .

Receptors and Signaling

Receptor Interactions

CCL3, also known as macrophage inflammatory protein-1α (MIP-1α), primarily binds with high affinity to the receptors CCR1 and . The (Kd) for CCL3 binding to CCR1 is approximately 1–5 , enabling potent activation of this receptor on immune cells. In contrast, the Kd for is around 3 , reflecting a slightly lower but still high-affinity interaction. CCL3 exhibits low affinity for but negligible binding to CCR3. As a promiscuous , CCL3 acts as an agonist for both CCR1 and , sharing these receptors with other CC chemokines such as (RANTES) and CCL7 (MCP-3) for CCR1, and (MIP-1β) and for . Notably, serves as a critical co-receptor for HIV-1 entry into target cells, and CCL3 to can inhibit viral fusion by competing with gp120. The N-terminal domain of CCL3 is essential for receptor engagement, interacting with the extracellular loops of CCR1 and to initiate recognition. Additionally, CCL3 can dimerize, but high-affinity to is primarily mediated by the monomeric form, with dimers showing reduced receptor- efficiency. Furthermore, CCL3 forms heterodimers with , which may interact with , potentially influencing signaling through cooperative effects at the receptor site. Receptor expression patterns influence CCL3's cellular targets: CCR1 is predominantly expressed on monocytes and neutrophils, facilitating their recruitment in inflammatory contexts, while CCR5 is mainly found on T cells, macrophages, and dendritic cells, supporting adaptive immune responses. These selective interactions underscore CCL3's role in orchestrating leukocyte trafficking without extensive overlap in downstream effects.

Downstream Pathways

Upon binding to its primary receptors CCR1 and , CCL3 initiates intracellular signaling primarily through G-protein coupling. Both CCR1 and CCR5 are seven-transmembrane G-protein-coupled receptors that preferentially couple to the inhibitory Gαi/o of heterotrimeric G-proteins, leading to the of Gαi from the Gβγ subunits upon engagement. This coupling is pertussis toxin-sensitive, confirming the involvement of Gαi/o, as demonstrated in functional assays with monocytes and T cells expressing these receptors. The activated Gαi subunit inhibits adenylate cyclase activity, resulting in decreased intracellular cyclic AMP () levels, which modulates downstream effectors in immune cells such as macrophages and T lymphocytes. Concurrently, the released Gβγ subunits activate phospholipase C β (PLCβ), which hydrolyzes (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 subsequently binds to IP3 receptors on the , mobilizing intracellular calcium (Ca²⁺) stores and elevating cytosolic Ca²⁺ concentrations, a critical step for chemotactic responses in CCR1- and CCR5-expressing cells. DAG, in turn, activates (PKC), amplifying the signaling cascade. These events have been characterized in detail using and biochemical assays in cell lines stably transfected with CCR1 or CCR5. CCL3 receptor engagement further triggers kinase activation, including the (MAPK) pathway leading to of 1 and 2 (ERK1/2), as well as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and / (JAK/) signaling. ERK1/2 occurs via Gβγ-mediated activation of kinases and the Ras-Raf-MEK cascade, promoting cytoskeletal rearrangements essential for cell motility in monocytes and tumor cells. PI3K/Akt activation, driven by Gβγ recruitment of class IB PI3K isoforms, enhances cell survival and migration, with Akt observed in esophageal lines stimulated with recombinant CCL3. JAK/STAT signaling involves direct of JAK2 by the receptor complex, independent of G-protein activation in some contexts, leading to STAT dimerization and nuclear translocation for gene regulation in T cells and macrophages. These kinase pathways have been validated through phosphospecific blots and studies in primary immune cells and CCR5-expressing models. Downstream of these kinases, CCL3 signaling induces changes in gene expression, notably via activation of the nuclear factor-κB (NF-κB) transcription factor. PKC and IKK complex activation lead to phosphorylation and degradation of IκB, allowing NF-κB p65/p50 heterodimers to translocate to the nucleus and upregulate pro-inflammatory genes. This results in increased expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on endothelial and synovial cells, facilitating leukocyte adhesion, and cytokines like interleukin-6 (IL-6) in fibroblasts and macrophages, amplifying inflammation. For instance, in rheumatoid arthritis synovial fibroblasts, CCL3 stimulation via CCR1/CCR5 enhances IL-6 production through NF-κB-dependent transcription, as shown by luciferase reporter assays and NF-κB inhibitors. ICAM-1 upregulation follows similar NF-κB-mediated mechanisms in response to CCL3 in inflammatory contexts. To prevent prolonged signaling, desensitization mechanisms are engaged following sustained CCL3 stimulation. G-protein-coupled receptor kinases (GRKs) phosphorylate serine/threonine residues in the C-terminal tail and intracellular loops of CCR1 and , recruiting β-arrestins. β-Arrestin binding uncouples the receptor from G-proteins, terminating Gαi-mediated signals, and promotes clathrin-mediated via adaptor protein-2 (AP-2) interaction, leading to receptor and lysosomal or . This has been elucidated using β-arrestin overexpression and assays in HEK293 cells expressing CCR5. CCL3 signaling also exhibits cross-talk with (TLR) pathways in innate immune cells like macrophages, where acts as a co-receptor enhancing TLR4-induced responses. In (LPS)-stimulated macrophages, ligation by CCL3 synergizes with TLR4/MyD88 signaling to boost inducible nitric oxide synthase (iNOS) expression and production, likely through shared activation, without altering baseline TLR signaling. This interaction underscores CCL3's role in amplifying innate responses during infection or .

Physiological and Pathological Roles

Normal Immune Regulation

CCL3 shows enhanced basal expression in , lymphoid s, and liver, contributing to the maintenance of resident populations under steady-state conditions. This constitutive expression supports innate immune by ensuring a stable presence of macrophages in these compartments, which are essential for homeostasis and monitoring without inducing overt . CCL3 influences hematopoietic stem and progenitor cell (HSPC) dynamics in the , inhibiting and promoting myeloid lineage commitment to support steady-state hematopoiesis and generation of mature myeloid cells. Studies in CCL3-deficient mice reveal largely normal immune , with no overt hematopoietic abnormalities or developmental defects under steady-state conditions. However, these mice display subtle impairments in myeloid , including reduced peripheral monocytes and granulocytes, alongside increased but less functional HSPCs. Notably, they exhibit minor defects in antiviral responses, such as delayed clearance, highlighting CCL3's nuanced role in fine-tuning immune readiness without disrupting basal equilibrium.

Disease Associations

CCL3, also known as macrophage inflammatory protein-1α (MIP-1α), is implicated in the of various inflammatory diseases through its role in recruiting immune cells to sites of . In (RA), CCL3 levels are elevated in , where it promotes the recruitment of and T cells, contributing to joint destruction and formation. Similarly, in (MS), CCL3 is expressed in active demyelinating plaques, facilitating the infiltration of inflammatory monocytes and T cells that exacerbate lesion formation and neurodegeneration. In infectious diseases, CCL3 exhibits dual roles depending on the context. It acts as a natural for HIV-1 entry by binding to the co-receptor on target cells, thereby suppressing viral infection in and T cells. In bacterial infections, CCL3 is protective by enhancing activation and bacterial clearance, as demonstrated in models of where CCL3-deficient mice showed increased susceptibility. However, excessive CCL3 production during can drive hyperinflammation and organ damage, with higher circulating levels correlating with disease severity in bacterial models. CCL3 contributes to cancer progression by modulating the tumor microenvironment, particularly through tumor-associated macrophages (TAMs). In breast cancer, TAM-derived CCL3 recruits myeloid-derived suppressor cells, promoting immune evasion and metastasis, with elevated CCL3 expression associated with advanced disease stages. In colorectal cancer, CCL3 secreted by cancer cells and hepatocytes enhances tumor cell proliferation, invasion, and osteoclastogenesis, facilitating bone metastasis and correlating with poor patient prognosis. Beyond these, CCL3 is involved in other conditions. In , it is upregulated in fluid, recruiting and exacerbating airway . In , CCL3 promotes monocyte adhesion to endothelial cells, accelerating plaque formation and lesion progression. For , elevated CCL3 levels in at-risk individuals (e.g., first-degree relatives) are linked to early autoimmune beta-cell destruction. Recent studies as of 2025 associate elevated CCL3 with adverse outcomes following , cognitive impairments in through microglial activation, and ferroptosis-mediated degeneration. Genetic variations in CCL3 further influence risk. Polymorphisms and haplotypes in the CCL3 on 17q12 are associated with increased RA susceptibility, with one haplotype showing significant (P = 7.56 × 10^{-5}). Similarly, higher copy numbers of the related CCL3L1 (>2 copies) confer elevated RA risk ( 1.34, 95% 1.08–1.66). In , CCL3 haplotypes are linked to susceptibility, underscoring its role in .

Clinical Significance

Biomarker Applications

CCL3, also known as macrophage inflammatory protein-1α (MIP-1α), is commonly measured in clinical settings using for detection in or samples. Normal levels in healthy individuals are typically below 50 pg/mL. Commercial ELISA kits offer sensitivity down to approximately 4–10 pg/mL to quantify these low baseline concentrations. For tissue-based analysis, quantitative (qPCR) is employed to assess CCL3 mRNA expression, providing insights into local production in inflamed or diseased tissues such as synovial or neural samples. In diagnostic applications, elevated serum CCL3 levels serve as an indicator for predicting disease flares in (), where concentrations above normal thresholds correlate with active inflammation and joint damage progression. Prognostically, high CCL3 expression in the signals aggressive disease behavior in cancers such as . In (DLBCL), serum CCL3 levels exceeding 40 pg/mL are associated with inferior overall survival, with hazard ratios indicating roughly twofold increased risk (e.g., HR ≈ 2.0) linked to advanced prognostic indices like the . Similarly, in (CLL), plasma CCL3 above 10 pg/mL independently predicts shorter time to treatment initiation and poorer outcomes. In clinical trials, CCL3 has been evaluated in inflammatory bowel disease (IBD). Elevated CCL3 levels in mucosal biopsies from patients with active and suggest a potential role as a for disease activity.

Therapeutic Targeting

Therapeutic targeting of CCL3, a key that signals primarily through CCR1 and receptors to recruit immune cells, has focused on modulating its activity to treat inflammatory, infectious, and neoplastic conditions. Antagonists aim to inhibit excessive CCL3-mediated , while agonists seek to enhance immune responses in or settings. These approaches leverage small molecules, antibodies, and nucleic acid-based interventions, though clinical translation remains challenged by the chemokine's pleiotropic roles in both and . Small molecule inhibitors of CCR1, a primary receptor for CCL3, have shown promise in reducing CCL3-driven in (RA). For instance, the CCR1 CCX354-C (vercirnon) was evaluated in the phase II CARAT-2 trial, where the 200 mg once-daily dose achieved an ACR20 response rate of 56% in the prespecified population (versus 30% for ), indicating clinical activity in improving joint symptoms and in methotrexate-treated patients. Similarly, earlier CCR1 antagonists like BX471 demonstrated blockade of CCL3-induced migration from RA , supporting their potential to dampen T-cell-driven , though clinical efficacy was modest due to challenges in achieving sustained receptor occupancy. Neutralizing monoclonal antibodies (mAbs) against CCL3 have been explored in preclinical models of allergic inflammation. In a murine model of allergen-induced , blockade of CCL3 with specific mAbs significantly reduced airway and during the early allergic response phase, highlighting CCL3's role in initial recruitment to the . CCR5 antagonists, which indirectly block CCL3 signaling by occupying its receptor, have established clinical utility in therapy; maraviroc, an FDA-approved CCR5 inhibitor, prevents HIV-1 entry into + T cells and inhibits CCL3 binding to , thereby disrupting both viral tropism and chemokine-mediated immune activation in infected individuals. Gene therapy strategies, such as siRNA-mediated knockdown of CCL3, have suppressed tumor progression in cancer models by limiting . In cell lines (MDA-MB-231 and MCF-7), CCL3 siRNA reduced expression by 80-90%, inhibiting , , , and S-phase progression while promoting ; , this approach diminished myeloid-derived suppressor cell recruitment and lung metastatic nodules in 4T1 tumor-bearing mice via disruption of the PI3K-Akt-mTOR pathway. As an agonist, recombinant CCL3 has been tested to enhance vaccine immunogenicity by attracting natural killer cells and CD8+ T cells. In murine models, co-delivery of CCL3 with adenoviral vectors encoding Friend retrovirus antigens boosted virus-specific antibody titers and CD4+ T-cell responses, improving protective immunity; similarly, CCL3 coexpression with HIV-1 Gag or HSV-2 antigens in DNA vaccines augmented T-cell recruitment and antitumor effects in gastric cancer models. Despite these advances, therapeutic targeting of CCL3 faces challenges, including off-target effects that impair normal immune surveillance, such as reduced + T-cell function or unintended suppression of antiviral responses. Ongoing efforts, including targeted delivery systems like recombinant AAV-mediated CCL3 expression in models, aim to minimize such risks while enhancing specificity, though no large-scale trials for CCL3 modulation in were active as of 2025.

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