Roles of chemokines in pancreatitis: A review

Abstract

Pancreatitis is one of the largest contributors to increased healthcare costs. It is widely accepted that exposure of acinar cells to injurious agents leads to necrosis and pancreatic enzyme activation. Inappropriate activation of trypsinogen in the pancreas is related to infiltration of leukocytes recruited by chemokines, which directly leads to acinar cell damage, and indirectly to a strong systemic inflammatory response. Otherwise, chemokines exert pleiotropic effects by recruiting immune cells during inflammation, immune surveillance, and directing cells to target organs in homeostasis. Here, we give a brief introduction to the basic molecular and cellular sources of chemokines, and focus on their pleiotropic functions in acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, and pancreatic cancer. Understanding the interaction between these processes is helpful for devising therapeutic strategies for pancreatitis.

Key Words: Pancreatitis; Inflammation; Chemokines; Protection; Aggravation

Core Tip: This review highlights the pivotal roles of chemokines in the pathogenesis of various types of pancreatitis, including acute, chronic, autoimmune, and pancreatic cancer. Chemokines like CCL2/MCP-1 and CXCL2 exacerbate acute pancreatitis by promoting neutrophil infiltration, whereas CXCL10 and CXCR3 contribute to chronic inflammation and fibrosis. CCL1-CCR8 interaction is critical for lymphocytic recruitment in autoimmune pancreatitis. Understanding the specific functions of these chemokines may lead to the development of novel therapeutic strategies targeting these inflammatory mediators.

INTRODUCTION

Pancreatitis is a major cause of hospitalization in China and is one of the largest contributors to healthcare costs. The underlying pathogenic mechanism of pancreatitis is still unknown to a large extent[1,2]. It is widely accepted that exposure of acinar cells to injurious agents leads to necrosis and pancreatic enzyme activation[3,4]. Inappropriate activation of trypsinogen in the pancreas is thought to be responsible for onset and aggravation of pancreatitis and pancreatic enzyme autodigestion[5-7]. Infiltration of leukocytes seems to be directly involved in the pathogenesis of trypsin-centered pancreatitis, which results in acinar cell damage, interstitial edema, and hemorrhage, which activates pathological inflammatory signaling and triggers other cellular molecular stress responses[8]. This may lead to a strong systemic inflammatory response, progressing from local pancreatic damage to multiple organ dysfunction, including acute respiratory distress syndrome, cardiovascular failure, renal failure and gastrointestinal hemorrhage[9-13].

The contribution of chemokines to the development of pancreatitis varies in different conditions. Beyond immune cell recruitment, chemokines modulate pancreatic stellate cell (PSCs) functionality during pancreatitis progression[14-18]. Comprehending how these processes interact is crucial for developing pancreatitis treatment approaches. Pancreatitis immunopathology is characterized by monocyte/neutrophil hyperactivation, driven by chemokine-mediated reactive oxygen species (ROS)/nicotinamide adenine dinucleotide phosphate oxidase oxidase cascades[19-25]. There is currently no literature to review the relationship between pancreatitis and chemokines. PubMed/MEDLINE, Web of Science, EMBASE, and Cochrane Library were searched for publications from January 2000 to December 2024 using the keywords "chemokines", "pancreatitis", and related terms. Original research articles, meta-analyses, and clinical studies with defined diagnostic criteria published in English were included, and case reports, non-controlled studies, duplicates, and non-chemokine-focused research were excluded. Two investigators independently screened titles and abstracts with third-reviewer arbitration.

MOLECULAR BASIS AND RECEPTORS OF CHEMOKINES IN PANCREATITIS

Chemokines are low-molecular-weight proteins that are pivotal in pancreatitis development and acinar cell demise (Figure 1). They are classified into four distinct families (CC, CXC, CX3C, and C) according to their N-terminal cysteine motifs[15,26]. Chemokine receptors represent classical G-protein-coupled transmembrane proteins and are present across diverse leukocyte populations in pancreatitis[27].

Figure 1 Pancreatic enzyme autodigestion and immunocyte-mediated inflammation. Molecular mechanisms involved in pancreatitis. In normal conditions, pancreatic enzymes aid digestion. However, during pancreatitis, inappropriate activation of trypsinogen leads to autodigestion within the pancreas, causing inflammation. This triggers the secretion of chemokines and other cytokines, which attract and activate immune cells, further amplifying the inflammatory response and exacerbating pancreatic damage.

Elevated plasma levels of interleukin (IL)-8, MIP-2/CXCL2, and monocyte chemoattractant protein (MCP)-1/CCL2, a hallmark inflammatory chemokine recruiting CCR2+ monocytes, T cells, and other targets-characterize early pancreatitis[15,28-31]. CCL2/MCP-1 neutralization reduces serum amylase and lipase levels and histopathological lesions, which could protect against pancreatic injury in CCR5^−/− mice[32]. Extracellular signal-regulated kinase (ERK) activation within the CXCL12-CXCR4 signaling axis underlies dorsal root ganglion (DRG) neuronal hyperexcitability, a key mediator of chronic pancreatic pain hypersensitivity. Intrathecal administration of the CXCR4 antagonist AMD3100 normalizes both Nav1.8 sodium channel upregulation and DRG neuronal hyperexcitability. AMD3100 significantly suppresses Nav1.8 activity via an ERK-dependent pathway[33]. CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4 sclerosing cholangitis/autoimmune pancreatitis (AIP), leading to duct-centered inflammation and obliterative phlebitis[34]. In acute pancreatitis (AP), macrophage-derived high-mobility group box (HMGB)1 drives pancreatic pain via dual activation of receptor for advanced glycation end-products (RAGE) and the CXCL12-CXCR4 axis. Extracellular HMGB1 binds RAGE/toll-like receptor (TLR) 4 to induce inflammation and complexes with CXCL12 to amplify CXCR4 signaling, exacerbating neuropathic pain. Neutralizing antibodies, ethyl pyruvate (inhibiting HMGB1 release), or liposomal clodronate (depleting macrophages) reversed cerulean-induced pain but not pancreatic injury, confirming the specific role of HMGB1 in nociception rather than tissue damage[35,36]. Damage-associated molecular patterns (DAMPs), including HMGB1, fibronectin extra domain-a (FN-EDA), galectin-3 (GAL3), and CXCR2, induce neutrophil extracellular traps (NETs) that exacerbate thrombosis in severe AP (SAP). These DAMPs activate neutrophils to release cytotoxic chromatin fibers that drive fibrin deposition and microvascular occlusion. HMGB1 synergizes with FN-EDA/GAL3 via TLR4/integrin pathways to amplify NETosis, while CXCR2 enhances NET release through IL-8 signaling. Targeting this DAMP-NET-thrombosis axis may mitigate SAP complications[37].

NEUTROPHILS AND MONONUCLEAR CELLS IN PANCREATITIS

Activated monocytes and macrophages secrete cytokines (Figure 2) that engage mesenchymal cells involved in tissue-specific wound repair, notably platelet-derived growth factor and transforming growth factor (TGF)-β1, which drive fibrogenesis[38]. Activated Kupffer cells release IL-1β along with neutrophil-attracting chemokines (CXCL1, CXCL2, CXCL8/IL-8), which play pivotal roles in neutrophil recruitment and AP pathogenesis. They release ROS as well as proteases and thereby evoke hepatocyte necrosis[39,40]. These findings imply that CCL2-induced migration and suppressor of cytokine signaling (SOCS)3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice. SOCS3-dependent activation and activated CD11b^highCD11c⁻ cells, including Gr-1^low macrophages and Gr-1^high cells (granulocytes and myeloid-derived suppressor cells), are increased in damaged pancreas after cerulein administration, but not in CCL2^−/− mice[41]. Neutrophils critically orchestrate pancreatitis progression by modulating trypsin activation, an initial step that enhances neutrophil infiltration, subsequently amplifying trypsin generation and NET release[42]. Therapeutic interventions targeting neutrophils significantly lower tissue damage and protect against the occurrence of pancreatitis[43]. Annexin V, a negative regulator of neutrophil influx and recruitment, stimulates macrophages to release anti-inflammatory cytokines, including transforming growth factor-beta (TGF-β) and IL-10, and suppresses the inflammatory response[44]. Neutrophil infiltration and trypsinogen activation are considered to play a pivotal role in the pathophysiology of SAP. The activation of trypsinogen to trypsin increases neutrophil infiltration into the pancreas. Inhibition of trypsin activation by deleting trypsinogen-7 or cathepsin B gene reduces pancreatic damage, along with neutrophil infiltration in mice[43].

Figure 2 Immune cell recruitment and cytokine storm in pancreatitis. During pancreatitis, chemokines attract and activate immune cells, including neutrophils, macrophages, and monocytes. The activated cells further secrete cytokines, exacerbating the inflammatory response and ultimately leading to a cytokine storm.

CHEMOKINES IN AP

AP is an inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes (Figure 3). Pancreatitis is divided into mild and severe forms[45]. AP usually is regarded as a mild and self-limiting illness, but 20%-30% of patients eventually develop SAP[46]. Pancreatic acinar cells release many inflammatory mediators including chemokines and oxygen free radicals[47,48]. It has been confirmed that combined treatment with resveratrol and guggulsterone reduces cerulein-induced mild AP in mice in a dose-dependent manner[49]. It has also been confirmed that the IL-10-1082A/G genetic variation contributes to risk of AP independent of population assessed, sample size, and patient/control selection[50]. Allograft inflammatory factor (AIF) 1 orchestrates macrophage functions—migration, phagocytosis, proliferation, survival, and proinflammatory activation. In AP, AIF1 expression is markedly upregulated, especially in SAP, and strongly correlates with activation of the NET formation pathway (KEGG), suggesting its role in SAP-associated immunothrombosis[16].

Figure 3 Chemokine-mediated activation of mononuclear cells in acute pancreatitis. During acute pancreatitis, various chemokines are involved in activating mononuclear cells, such as monocytes, neutrophils and macrophages. These chemokines, including CCL2, CXCL10, CCL5, CXCL16, CXCL1, CXCL2, and CXCL8, play crucial roles in regulating their activities.

Mononuclear and neutrophil chemotactic factors aggravate AP

CCL2/MCP-1 is produced by pancreatic acinar cells and upregulated during experimental AP. Recent studies have demonstrated that both CXCL2 and CCL2 are elevated in the plasma of patients with AP, and may participate as early triggers for inducing the inflammatory cascade[51]. Blocking of CCL2/MCP-1 synthesis protects mice against AP. Treatment with DL-propargylglycine, downregulates cerulein-induced increase in MCP-1, MIP-1α, and MIP-2 expression. Proinflammatory effect of H₂S in AP may be mediated by chemokines[52]. Meta-analytic evidence from six ethnic-based studies revealed that the CCL2-2518 A/G polymorphism exhibits significant associations with pancreatitis susceptibility, particularly in SAP patients vs controls[53]. The protection induced by CCL2/MCP-1 neutralization against pancreatic injury seems to be only partial and milder than that following simultaneous CCL2, CCL3, CCL4, and CCL5 neutralization, because it does not abolish the exacerbation in pancreatic damage observed in CCR5^−/− mice. CCR5 deficiency exacerbates the severity of injury during cerulein-induced experimental AP[32]. Human immunodeficiency virus (HIV) proteins induce oxidative and endoplasmic reticulum stresses, causing necrosis. Necrotic products activate PSC upon interaction, triggering the release of inflammatory and profibrotic cytokines that ultimately induce pancreatitis. HIV entry via CCR5 into pancreatic acinar cells could additionally play a role in pancreatitis development among individuals with HIV. This suggests that HIV-induced pancreatitis may be AIP. CXCL10 has been shown to induce apoptosis in pancreatic acinar cells[54]. CCL2 and CCL4 are major chemoattractants for granulocytes and monocytes; therefore, suppressed expression of CCL2 and CCL4 may play a key role in the anti-inflammatory effects of AP[55]. The pathology of SAP in mice mirrors that of human AP, and is characterized by lung and kidney dysfunction. This organ injury is mediated by Ly6G^-/CD11b⁺/Ly6C^hi monocytes, not Ly6G⁺/CD11b⁺ neutrophils. Selective monocyte depletion via anti-CCR2 antibodies improves pulmonary oxygenation without compromising systemic immunity. Clinically, AP severity correlates with elevated monocyte-recruiting chemokines [e.g., MCP-1/CCL2, monokine-induced interferon g (MIG)/CXCL9] and leukocyte mobilization in patients, aligning with murine mechanistic findings[56].

Chemotactic receptors mediate AP

BX471-mediated CCR1 blockade significantly reduces intercellular adhesion molecule 1 (ICAM-1), P-selectin, and E-selectin expression at both transcriptional and translational levels in pulmonary and pancreatic tissues relative to vehicle controls. Interfering with neutrophil migration and activation by targeting CCR1 may be a promising strategy to prevent disease progression in AP[57]. The deletion of another receptor for MIP1α and RANTES, the CCR1 receptor, is associated with protection from pulmonary inflammation secondary to AP in mice, associated with decreased levels of TNF-α in a temporal sequence[58]. CXCR3 deficiency mitigates AP-induced acute lung injury, as demonstrated by attenuated pulmonary damage in CXCR3 knockout murine models of experimental pancreatitis[59] induced by retrograde infusion of sodium taurocholate into the pancreatic duct in wild-type, TLR2- and TLR4-deficient mice. While TLR2 knockout mice exhibited comparable responses to wild-type controls upon taurocholate challenge, TLR4-deficient mice demonstrated markedly attenuated tissue injury, reduced pancreatic/pulmonary myeloperoxidase (MPO) activity, diminished CXCL2 levels in serum and pancreas, and lower blood amylase. Notably, taurocholate-triggered trypsinogen activation remained unaffected in TLR4-deficient animals[60].

CXCL1 and CXCL2 chemokines play different roles in AP

Hypothermia synergistically and simultaneously slows parallel and distinct signaling steps initiated by cerulein induction of inflammatory mediators and acinar injury. There was > 80% reduction in triglycerides (TGA), CXCL1 and CXCL2 mRNA levels at 29 °C, and in cell injury. Trypsin activity, cathepsin B activity and cathepsin-B-mediated TGA activity at 23 °C were 53%, 64% and 26% of that at 37 °C, respectively[61]. These results indicate that thrombin-derived host defense peptides (TDPs) provide dual protection by mitigating inflammatory pathology and cellular injury in AP, with potential clinical applications in SAP. TDP treatment significantly suppresses taurocholate-elevated plasma CXCL2 and IL-6 concentrations in C57BL/6 mice. The peptides also reduce histone 3/4 and MPO accumulation while completely inhibiting Mac-1 expression on neutrophils during pancreatitis. Furthermore, TDPs demonstrate direct inhibitory effects on CXCL2-mediated neutrophil chemotaxis in vitro[62]. Pre-administration of the geranylgeranyltransferase inhibitor GGTI-2133 significantly attenuates taurocholate-induced AP in male C57BL/6 mice, as evidenced by reduced plasma amylase activity, diminished pancreatic neutrophil infiltration, and suppression of hemorrhage/edema formation. The inhibitor also mitigates MPO activity elevation in both pancreatic and pulmonary tissues. Notably, GGTI-2133 treatment dramatically lowers taurocholate-stimulated CXCL2 production in pancreatic tissue and IL-6 secretion in plasma, suggesting geranylgeranyltransferase inhibition as a potential therapeutic strategy for SAP[63]. CXC chemokine inhibition with evasin-3 improves neutrophil inflammation and injury in AP. Treatment with evasin-3 decreases neutrophil infiltration, ROS production and apoptosis in the lungs, and reduces neutrophil and macrophage apoptosis and necrosis in the pancreas[64]. Exogenous leptin attenuated inflammatory changes, and reduces proinflammatory cytokines, NO levels and CD40 expression in cerulein-induced AP, and may be protective in AP-associated acute lung injury. In the leptin group, serum levels of MIP-2, soluble ICAM-1, tumor necrosis factor (TNF)-α, and IL-1β, pancreatic MPO activity, CD40 expression in pancreas and lung tissues, and NOx level in lung tissue were lower compared to those in the AP group. Histologically, pancreatic and lung damage was less severe following leptin administration[65]. The putative pancreatic progenitor cells (Pdx1^high/Shh^low cells) derived from mouse embryonic stem cells through the treatment of CXCR4⁺ cells in vitro with basic fibroblast growth factor, exendin-4, and cyclopamine improved the regeneration of injured pancreatic acini in vivo. These cells specifically reside in the damaged pancreas acinar area in mice with AP to enhance regeneration of the pancreas[66]. Panhematin at moderate doses demonstrates therapeutic potential for human pancreatitis through rapid HO-1 activation and HO-1+ cell recruitment, effectively reducing leukocyte infiltration and CXCL1 expression, even with delayed post-onset administration[67].

Relevant signaling pathways of chemokines in AP

Dual inhibition of nuclear factor (NF)-κB and activator protein-1 (AP-1) can completely suppress MIP-2 upregulation, and is a successful strategy to reduce inflammation in pancreatitis compared with targeting NF-κB alone. Neutrophil chemoattractants, the CXC-ELR chemokines keratinocyte cytokine (KC) and MIP-2 have NF-κB and AP-1 binding sites in their promoter regions. NF-κB inhibition completely prevents upregulation of KC but not MIP-2[68]. Fatty acids are released from peripancreatic fat during AP, which induces an inflammatory response in pancreatic acini. The most common unsaturated fatty acids in peripancreatic fat and released during AP upregulate the acinar expression of CCL2, which depends on activation of the mitogen-activated protein kinase (MAPK)/Janus kinase-mediated NF-κB and STAT3 pathways (Figure 4)[69]. CXCL10 induced a 3.9-fold increase in apoptosis when administrated at an optimal dose for 8 h in human pancreatic acinar cell cultures. The contribution of upstream apoptotic regulators, such as phosphorylated C-Jun N-terminal kinase (pJNK), p38, and Bax, was demonstrated by their heightened CXCL10 expression. CXCL10 triggers apoptotic cell death in cultured human pancreatic cells through ATP depletion and CXCR3-mediated signaling, resulting in DNA fragmentation. These signaling pathways likely contribute significantly to parenchymal cell damage and loss during pancreatitis[70]. Exposure to TNF-α or poly (I:C) upregulated pancreatitis-associated chemokines MCP-1 and CX3CL1, while concurrently elevating intracellular/mitochondrial ROS and NF-κB activity, but diminishing mitochondrial membrane potential[71].

Figure 4 The signaling pathways involved in pancreatitis pathogenesis. Upon pancreatitis onset, fatty acids released from peripancreatic fat induce expression of chemokines, including CCL2, MIP-2, and CXCL12, in pancreatic acinar cells via MAPK/JAK-mediated NF-κB and STAT3 pathways. Additionally, CXC-ELR triggers activation in mononuclear cells through CXCR3 signaling and activation of upstream regulators like pJNK, p38, and Bax, leading to the occurrence of pancreatitis. Inflammatory stimuli such as NETs or inflammation-related signaling pathways such as MAPK, JNK/STAT, INF-γ/AP-10, and ERK/SIRT1, enhance chemokine expression, accompanied by ROS, myeloperoxidase, AIF1, ONx production and NF-κB activation, exacerbating the inflammatory response. These signaling mechanisms collectively contribute to acinar cell damage, immune cell recruitment, and the progression of pancreatitis.

Other chemokines play different roles in AP

CXCL16 is superior in predicting infected pancreatic necrosis when compared to C-reactive protein and TNF-related activation-induced cytokine (TRANCE) in patients with pancreatic necrosis[72]. IL-17A is a proinflammatory cytokine whose expression was significantly increased following induction of experimental AP by 3% sodium taurocholate. Emerging evidence indicates that IL-17A contributes to pancreatic injury pathogenesis through modulation of inflammatory cytokine and chemokine networks in experimental AP. Recombinant IL-17A induces rat pancreatic acinar cell necrosis and promotes expression of several target genes, including IL-6, IL-1β, CXCL1, CXCL2, and CXCL5, in acinar cells and PSC[73]. Experimental evidence demonstrates that CXCL4 significantly contributes to pancreatic inflammatory responses in AP, where targeted CXCL4 inhibition effectively attenuates taurocholate-induced pathological changes. This intervention reduces neutrophil infiltration, suppresses systemic and pulmonary CXCL2 expression, decreases IL-6 production, and mitigates pancreatic edema, amylase release, and histopathological damage in C57BL/6 mouse models[74]. (R)-4,6-dimethoxy-3-(4-methoxyphenyl)-2,3-dihydro-1H-indanone, also known as (R)-TML104, significantly inhibited the expression of pancreatic chemokines CCL2 and MIP-2, as well as the infiltration of neutrophils and macrophages. This was achieved by activating AMP-activated protein kinase, inducing the interaction of STAT3, reducing acetylation of STAT3, and inducing expression of SIRT1[75].

Activation of trypsinogen in AP

The molecular pathways controlling both trypsinogen activation and inflammatory responses in AP remain poorly characterized. Activation of trypsinogen by secretagogues in acinar cells is prevented by NF of activated T-cells cytoplasmic 3 inhibitor A-285222. A-285222 reduces taurocholate-induced increases in levels of amylase, MPO, and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas of mice[76]. Histone deacetylase (HDAC) inhibition reduces cerulein-induced trypsinogen activation in isolated acinar cells. Thus, targeting HDAC could serve as a novel therapeutic approach in the management of SAP[77]. Immunoneutralization of P-selectin decreases the taurocholate-induced increase in serum trypsinogen, neutrophil accumulation and tissue damage. Targeting P-selectin may be an effective strategy to ameliorate inflammation in AP[78]. Genetic ablation of MMP-9 in mice completely prevents taurocholate-induced pancreatic pathology, including elevated amylase levels, neutrophil infiltration, CXCL2 production, trypsinogen activation, and tissue damage. These results establish neutrophil-derived MMP-9 as a critical mediator of trypsinogen activation in acinar cells and a key regulator of inflammatory responses and tissue injury in AP[79]. Bone-marrow-derived mesenchymal stem cells (BMSCs) prevent the progression of AP by reducing the recruitment of macrophages, neutrophils, and CD4⁺ T cells to the lesion site. The pivotal role of the chemokine-iNOS-IDO axis in the intervention of AP by BMSCs has been confirmed[80]. Q10 reduced pancreatic infiltration of monocytes and neutrophils while upregulating pancreatic levels of CCL2 and CXCL2 in AP mice. It ameliorated pancreatic injury and secondary pulmonary damage by suppressing proinflammatory cytokine production and inflammatory cell recruitment. Furthermore, Q10-mediated attenuation of AP was likely mediated through ERK/JNK pathway inactivation[81]. It was found that the levels of CXCL-1, MCP-1, and IL-6 were significantly higher in rats with pancreatitis. In correlation analyses, MCP-1 and IL-6 exhibited a moderate correlation with the severity of pancreatitis[15]. Secreted protein acidic and rich in cysteine (SPARC)^+/+ pancreatic tissue demonstrated significantly elevated levels of immune cell-derived CCL2, establishing SPARC as a modulator of AP severity. The SPARC-CCL2 axis mechanistically links stromal activity to inflammatory progression, positioning it as a promising target for precision-targeted therapy in AP management[82]. CCR8 expression demonstrated a severity-dependent upregulation, escalating from mild to moderately severe AP and SAP. RT-PCR confirmed a Log¹⁰-transformed CCR8 upregulation of 3-6 orders of magnitude (1000-1000000-fold) in moderately severe AP/SAP vs controls. The concomitant elevation of CCR8 and IL-6 in SAP patients, coupled with disease-stage-specific immune cell profiles, provides a mechanistic basis for developing severity-stratified management strategies in AP[30]. Pancreatitis-associated proteins (PAPs) mediate neuropathic pain via CCR2-dependent activation of spinal microglia. Pharmacological inhibition of either microglial priming or CCR2 signaling abrogates PAP-induced hyperalgesia, identifying this axis as a therapeutic target for pain modulation in pancreatitis[83].

CXCR4 facilitates repair of injured pancreas

The interaction of locally produced stromal cell-derived factor (SDF)-1 with CXCR4 on BMSCs has an important regulatory role in the migration of BMSCs towards the injured pancreas in AP. The SDF-1/CXCR4 signaling axis promotes pancreatic regeneration, an effect which was significantly attenuated through anti-CXCR4 antibody blockade in a rat model of taurocholate-induced pancreatic injury via bile duct retrograde infusion[84]. The findings demonstrate that SDF-1α markedly upregulates VEGF, angiotensin-1, HGF, TGF-β and CXCR4 expression in BMSCs, an effect effectively blocked by the receptor antagonist AMD3100. In vivo, studies demonstrate that BMSC migration is governed by the SDF-1α/CXCR4 axis. Transplanted BMSCs markedly attenuated SAP severity, diminishing systemic inflammation (TNF-α, IL-1β, IL-6) while enhancing tissue regeneration through angiogenic factors (VEGF, angiotensin-1, HGF, TGF-β, CD31), with superior efficacy compared to SAP and anti-CXCR4 controls, collectively confirming the axis' pivotal role in SAP repair[85]. Pancreatic tissue from patients with IgG4-related disease (IgG4-RD) exhibited marked overexpression of SDF-1/CXCL12 compared to healthy controls. Pharmacological targeting of the CXCL12/CXCR4/CXCR7 axis emerges as a promising strategy to disrupt pathogenic triad in IgG4-RD: Inflammatory cell infiltration, fibrotic remodeling, and NET accumulation, thereby addressing core disease mechanisms[86].

CHEMOKINES IN CHRONIC PANCREATITIS

Chronic pancreatitis (CP) is a disease of the pancreas, with loss of its exocrine and endocrine functions[87]. The pancreas is infiltrated by lymphocytes in CP and this is at least partially mediated by upregulation of chemokines in the inflamed pancreas[88]. Chronic pancreatic damage, predominantly induced by alcohol abuse, metabolic disorders, or autoimmune responses, triggers persistent inflammation that progressively replaces functional parenchyma with fibrotic scar tissue, culminating in organ dysfunction[89]. The existence of CXCL10 and CXCR3 with other CXC/CC chemokines (CXCL9, CXCL11, CCL3, CCL4, and CCL5) in CP is suggestive of their vital role in the progression of chronic inflammation. Real-time PCR has revealed increased expression of CXCL10 (13-fold) and CXCR3 (7-fold) and CCR5 in CP, which reveals their upregulation in the diseased state[90]. The increase in central memory T lymphocytes may be important for maintaining the inflammatory process in CP. Patients with CP, compared to healthy controls, have an increased level of CCR7⁺/CD45RA⁻ central memory T lymphocytes[91]. The activation of CXCL12-CXCR4 signaling might contribute to pancreatic pain and ERK-dependent Nav1.8 upregulation might lead to hyperexcitability of the primary nociceptor neurons in rats with CP. Intrathecal application of AMD3100, a potent and selective CXCR4 inhibitor, reversed the hyperexcitability of DRG neurons innervating the pancreas of rats following trinitrobenzene sulfonic acid injection[33]. Experimental evidence indicates that MCP-1 promotes immune polarization toward a Th2-dominant response pattern. MCP-1 can potentially regulate angiogenesis in the setting of chronic tissue damage. MCP-1 inhibitors may prevent fibrosis in CP that requires long-term treatment[92]. The CCR2/CCL2 axis-dependent recruitment of CD11b⁺ cells to pancreatic tissue plays a pivotal role in CP-induced hyperglycemia, primarily by altering GLP-1 receptor expression dynamics and impairing insulin secretory function. A significantly higher hyperglycemia level in chronic cerulein-administered CCR2 knockout mice was markedly restored by treatment with GLP-1[93]. CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially proliferation, where CX3CL1 levels are elevated. CX3CL1 induces proliferation of activated PSCs without increasing release of inflammatory mediators[94]. Ethanol synergistically increases CX3CL1 release via ERK and ADAM17 activation in PSCs. CX3CL1 release is suppressed by specific inhibitors of ERK, and ERK is associated with CX3CL1 transcription[95]. Recombinant CXCL9 ameliorates pancreatic fibrogenesis in 2,4,6-trinitrobenzenesulfonic acid-induced CP models, while in vitro analyses confirm its antifibrotic activity through inhibition of collagen synthesis in activated PSCs, suggesting therapeutic potential for pancreatic fibrosis intervention[96]. CCL20, IL-17, and ST1A1 serve as discriminators between chronic AIP (CAIP) and CP, providing a molecular basis for distinguishing CP from CAIP in clinical diagnostics. Notably, spatial transcriptomic profiling of hereditary CP patients undergoing total pancreatectomy islet autotransplantation has pinpointed CCL20 as a pathognomonic chemokine signature in pancreatic tissue, implicating its role in disease-specific immune dysregulation[97]. CP is defined by progressive, irreversible fibroinflammatory destruction of pancreatic parenchyma. Neddylation inactivation triggers an HIF-1α-dependent surge in CCL5 secretion, which drives chemotactic recruitment of M2-polarized macrophages into inflamed pancreatic tissue. This feed-forward cascade amplifies stromal fibrosis and disease progression through sustained macrophage-mediated inflammation. Therapeutic intervention via CCL5 neutralization (e.g., using CCR5 antagonists) or selective macrophage depletion significantly attenuates pancreatic fibrogenesis and inflammatory burden in MLN4924-induced CP murine models, identifying the neddylation-CCL5-macrophage axis as a key target for antifibrotic therapy[98]. Activated PSCs are central mediators of CP pathogenesis. Polyinosinic-polycytidylic acid stimulation upregulates PSC-derived MCP-1/CCL2 and fractalkine (CX3CL1); chemokines that orchestrate monocyte/macrophage infiltration and inflammatory cell trafficking in CP. This TLR3 agonist-driven chemokine induction establishes a profibrotic niche by recruiting CCR2⁺ and CX3CR1⁺ immune cells, thereby amplifying PSC activation and perpetuating pancreatic fibroinflammation[71]. Growing evidence confirms that gut microbiota imbalance plays a pathogenic role in gastrointestinal diseases. This study investigates causal interactions among intestinal flora, systemic inflammatory mediators, and CP. CCL23 level is positively associated with CP risk[99]. Similarly, the serum level of IL-17A and CCL20 differentiated CP from CAIP, suggesting the involvement of Th17 cells in CP pathogenesis[97]. CP patients with a history of AP have significantly higher serum levels of proinflammatory cytokines (IL-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (cutaneous T-cell attracting chemokine), MIG, macrophage-derived chemokine, and MCP-1 compared to CP without preceding AP and controls (Figure 5)[86].

Figure 5 Molecular mechanisms involved in pancreatitis. The figure illustrates several chemokines molecular mechanisms for the pancreatitis. These include macrophage-mediated production of inflammatory cytokines to impair pancreatic cells, causing trypsin spillage that leads to multiple organ dysfunction, and chemokines to attract immune cells, such as T-cell chemokines CCL3, CCL4, CCL5, CCL17, and CCL22, and neutrophil chemokines CXCL2 and CXCL8. Simultaneously, activated T cells secrete CCL1 to attract neutrophils and fibroblasts. Proinflammatory factors secreted by injured cells, such as: CXCL1, CXCL2, CXCL5, oxygen free radicals, and trypsin, can also activate neutrophils. Activated neutrophils can directly secrete myeloperoxidase, reactive oxygen species, nicotinamide adenine dinucleotide phosphate oxidase, and granular enzymes to impair many organs. Macrophages also secrete CXCL9 to prevent fibrosis of the pancreas, CX3CL1 to promote pancreatic hyperplasia, and CXCL10 and CX3CL1 to inhibits direct damage of macrophages. IL: Interleukin; MPO: Myeloperoxidase; TLR: Toll-like receptor.

CHEMOKINES IN AIP

CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centered inflammation and obliterative phlebitis. IgG4-SC/AIP are characterized by massive lymphocytic infiltration including Th2 and regulatory T cells. In conjunction with higher expression levels of IL-4 and IL-10, expression of CCL1 and CCR8 transcripts was significantly higher in IgG4-SC/AIP than in IgG4^low PSCs. CCL1 and CCR8 are also overexpressed in IgG4^high PSCs than in IgG4^lowPSCs but not CCL17, CCL22 and CCR4[34]. IFN-γ-induced protein (IP)-10 and these cells might play a key role in the development of chronic AIP. IP-10 neutralization ameliorated the pancreatic lesions of mice with murine-acquired acquired immunodeficiency syndrome; probably by blocking the cellular infiltration of CD4⁺ T cells and IFN-γ⁺ Mac-1⁺ cells into the pancreas. Anti-IP-10 antibody treatment significantly reduces IFN-γ⁺ and IL-10⁺ CD4⁺ T cells and IFN-γ⁺ Mac-1⁺ cells, in the pancreas[100]. The diagnostic utility of immunological markers (IgG4, CXCR5, CXCL13) in distinct pathological contexts, with CXCR5⁺ and CXCL13⁺ cell infiltration predominantly observed in autoimmune pancreatocholangitis cases[101]. The molecular mechanisms underlying poly (I:C)-induced murine AIP/IgG4-RD remain incompletely elucidated. Some findings demonstrate that these cells recruit CXCR3⁺ T cells to pancreatic tissue through CXCL9/10 secretion. Locally produced IFN-α then stimulates these T cells to generate CCL25, which mediates CCR9⁺ pDC recruitment, thereby sustaining pancreatic inflammation[102].

CHEMOKINES IN PANCREATIC CANCER

Pancreatic cancer (PCa) has a dismal prognosis because it is often diagnosed at an advanced stage[103]. CXCL16 and its receptor CXCR6 seem to play an important role in the pathobiology of PCa and might be potential diagnostic markers and a target for multimodal therapy in the future. Elevated CXCL16/CXCR6 expression in pancreatic ductal adenocarcinoma (PDAC) and CP vs normal pancreatic tissue. Functional studies demonstrate CXCL16-driven enhancement of PDAC cell invasion, with 82.5% of patients exhibiting serum CXCL16 levels surpassing the upper normal limit[104]. CP is one of the most important risk factors for PCa. A major difficulty is to distinguish between CP and PCa at both clinical and morphological levels. Expression of CCL20 is significantly higher in PCa than in CP. CCL20 plays a putative role during pancreatic tumorigenesis, and may therefore be a new parameter for histological diagnosis and discrimination between PCA and CP[105]. While CCL20/CCR6 exhibit minimal expression in normal pancreas and pancreatitis specimens (CP/AP), their mRNA and protein levels show 8-fold upregulation in PCa vs adjacent normal tissue, with strong correlation to advanced tumor stage, suggesting therapeutic targeting potential[106]. IL-8 and CXCL5 demonstrate dramatic overexpression in pancreatic carcinoma (66-fold and 24-fold vs cystadenoma; 6-fold and 9-fold vs CP), with expression levels strongly correlating to tumor stage, implicating their pathogenic role in disease progression[107]. The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. IFN-γ has multiple effects on many cell types within the PCa microenvironment that may lead to immune evasion, chemoresistance, and shortened survival. IFN-γ is central to effective antitumor immunity, and induces high levels of CXCL10 from all cell types, which can induce resistance to gemcitabine[108]. Extracellular MIF induces chemotaxis of monocytes, neutrophils, and T cells via MIF/CXCR2 and MIF/CXCR4 interactions. In AP, MIF-triggered monocyte arrest requires CD74 and MIF/CXCR2 or MIF/CXCR4 complex formation. This process is inhibited by MIF deficiency or antibodies targeting MIF, CXCR2, or CD74. Additionally, MIF binds CXCR7, promoting receptor internalization, activating ERK1/2-ZAP70 signaling, and stimulating B cell migration[17].

CLINICAL APPLICATION TRANSFORMATION AND CHALLENGES

The translational potential of chemokine-targeted therapies in pancreatitis faces both opportunities and hurdles. While preclinical studies demonstrate efficacy in modulating immune responses, clinical application requires addressing key challenges. Chemokines differ across AP, CP, and AIP, necessitating tailored diagnostics. Delivery precision targeting pancreatic tissue without systemic immunosuppression remains technically complex. And biomarker validation for current chemokine signatures needs multicenter validation for clinical utility. Additionally, combinatorial strategies may enhance efficacy but require rigorous safety evaluation. Bridging these gaps demands collaborative trials to transform mechanistic insights into standardized therapies (Table 1).

Table 1 Role of chemokines in pancreatitis diseases.

Disease model	Species of chemokines	Strategies	Trial results	Effect of trial	Ref.
Acute pancreatitis	CCL2	Anti-CCL2/MCP-1	Decreased serum amylase, lipase levels and histopathological lesions	Protective	[24]
Acute pancreatitis	CCL5	Anti-CCL5	Decreased serum amylase, lipase levels and histopathological lesions	Protective	[24]
Acute pancreatitis	CCR5	CCR5KO	Exacerbating the severity of pancreatic injury in vivo	Exacerbates in CCR5 KO pathogenic	[24]
Acute pancreatitis	CCL2	CCL2 KO	Activation and activated CD11b(high)CD11c (-) cells increased	Protective	[32]
Acute pancreatitis	CCR1	CCR1 inhibitor	Down-regulation of ICAM-1, P-selectin, and E-selectin	Protective	[44]
Acute pancreatitis	CXCR3	CXCR3 KO	Attenuated lung injury	Protective	[46]
Acute pancreatitis	CXCL2/ CXCL8	Anti-CXCL2/CXCL8	Abolished chemotaxis of neutrophils	Protective	[55]
Acute pancreatitis	CXCL4	Anti-CXCL4	Reduced neutrophil recruitment, levels of CXCL2 secretion, amylase release, and tissue damage	Protective	[60]
Acute pancreatitis	CXCR4	Anti-CXCR4	Migration of bone marrow mesenchymal stem cells	Pathogenic	[65]
Acute pancreatitis	CXCR4	CXCR4 agonist	Reducing the systematic inflammation, and promoting tissue repair and angiogenesis in vivo	Protective	[66]
Chronic pancreatic	CXCL12-CXCR4	CXCR4 inhibitor	Reversing the upregulation of Nav1.8 sodium channels in DRGs and hyperexcitability of DRG neuron	Protective	[25]
Chronic pancreatitis	CCR2	CCR2-KO	Promoting higher hyperglycemia level CD11b(+)-cell migration	Protective	[73]
Chronic pancreatitis	CX3CR1	rCX3CL1	Inducing the PSCs proliferation in pancreatitis	Protective	[74]
Chronic pancreatitis	CXCL9	rCXCL9	Attenuating fibrogenesis suppressing collagen production	Protective	[76]
Autoimmune pancreatitis	IP-10	Anti-IP-10	Reducing IFN-gamma+ and IL-10+ CD4+ T cells and IFN-gamma+ Mac-1+ cells migration	Protective	[77]
Injured pancreatic acini	CXCR4	Anti-CXCR4	Improve the regeneration of injured pancreatic acini	Protective	[53]
Primary human pancreatic acinar cell cultures	CXCL10	RecCXCL10	Promoting pancreatic acinar cel apoptosis and DNA fragmentation	Protective	[57]
Acute pancreatitis	CXCL12	Anti-CXCL12	Reversed cerulean-induced pain but not pancreatic injury	Protective	[35]
Acute pancreatitis	HMGB1	Ethyl pyruvate	Reversed cerulean-induced pain but not pancreatic injury	Protective	[36]
Acute pancreatitis	HMGB1	Targeting this DAMP-NET-thrombosis axis	Mitigated SAP complications	Protective	[37]
Acute pancreatitis	CCR2	Anti-CCR2	Improved pulmonary oxygenation without compromising systemic immunity	Protective	[56]
Acute pancreatitis	CCR8	Anti-CCR8	Reduced IL-6 level	Protective	[30]
Acute pancreatitis	CCR2	Anti-CCR2	Abrogated PAP-induced hyperalgesia	Protective	[83]
Acute pancreatitis	CXCL12	Anti-CXCL12. Anti-CXCR4. Anti-CXCR7	Disrupt pathogenic triad in IgG4-RD: Inflammatory cell infiltration, fibrotic remodeling, and neutrophil extracellular trap accumulation	Protective	[86]
Chronic pancreatitis	CCL5	Anti-CCL5	Significantly attenuated pancreatic fibrogenesis and inflammatory burden	Protective	[98]
Chronic pancreatitis	CCL2 CX3CL1	Anti-CCL2 Anti-CX3CL1	Mitigated PSC activation and perpetuating pancreatic fibroinflammation	Protective	[71]
Autoimmune pancreatitis	CXCL9/10	Anti-CXCL9/10	Attenuated CCR9+ pDC recruitment, thereby sustaining pancreatic inflammation	Protective	[102]

PSC: Pancreatic stellate cell; SAP: Severe acute pancreatitis.

CONCLUSION

Chemokines play pivotal roles in pancreatitis pathogenesis through their pleiotropic effects on immune cell recruitment and inflammatory responses. Targeting specific chemokine pathways shows therapeutic potential across different pancreatitis types, warranting further clinical investigation.