Endothelial Atypical Receptors for Chemoattractants in Lung Immune Surveillance

ABSTRACT

Chemokines and their receptors play a pivotal role in the initiation and regulation of inflammation through the orchestration of leukocyte extravasation and directed migration toward sites of tissue injury. Tight control of chemokine gradients within tissues is essential to ensure that inflammatory responses remain transient and properly resolved. When this regulatory mechanism fails, dysregulated chemokine signaling can contribute to the development of chronic inflammation. Atypical receptors for chemoattractants comprise atypical chemokine receptors (ACKRs) and the chemerin‐presenting receptor CCRL2. ACKRs perform specialized functions enabling the fine‐tuning of chemokine gradients, primarily through the scavenging, sequestration, or redistribution of chemokines. By regulating their spatial and temporal availability, ACKRs play a key role in limiting excessive leukocyte recruitment and promoting inflammation resolution. The lungs are in a dynamic equilibrium between immune activation and homeostasis. Rapid and tightly regulated immune cell recruitment is essential for effective host defense while preventing tissue damage. In this context, ACKRs expressed by specialized lung endothelial cells are emerging as critical regulators of leukocyte trafficking and inflammatory resolution. Given the paucity of studies in this area, this review summarizes current knowledge of ACKRs and CCRL2 in lung immune surveillance and discusses their potential as therapeutic targets in lung diseases.

Control of chemokine gradients within tissues is achieved by atypical chemokine receptors (ACKRs). The lungs require tightly regulated leukocyte recruitment for effective host defense while preventing tissue damage. In this context, ACKRs expressed by lung endothelial cells are emerging as critical regulators of leukocyte trafficking and inflammatory resolution.

1. Introduction

The coordination of immune responses within tissues relies on the precise regulation of leukocyte trafficking, a process that is tightly controlled to ensure effective host defense while preventing excessive inflammation [1, 2, 3, 4, 5, 6, 7]. In barrier organs such as the lung, this balance is particularly critical, as continuous exposure to environmental stimuli requires rapid immune activation coupled with efficient resolution mechanisms. Failure to maintain this equilibrium can result in chronic inflammation and tissue damage.

The lung represents a highly specialized immunological environment, where structural and cellular organization contributes to the fine control of immune cell recruitment. In particular, the vascular compartment plays a central role in orchestrating leukocyte entry into the tissue. Endothelial cells (ECs), positioned at the interface between circulation and parenchyma, actively regulate immune cell extravasation and distribution, thereby shaping local inflammatory responses [8, 9].

In recent years, atypical chemokine receptors (ACKRs) have emerged as key regulators of chemokine‐driven processes [2, 10, 11]. Unlike canonical chemokine receptors, ACKRs do not couple to heterotrimeric G proteins and therefore do not initiate G protein‐dependent signaling. Instead, they can recruit β‐arrestins, which promote receptor internalization and, for most ACKRs, ligand scavenging [2]. In ECs, the importance of chemokine‐induced β‐arrestins recruitment to ACKRs for intracellular signaling remains to be determined. CCRL2 shares the inability to activate G protein‐dependent signaling but differs from bona fide ACKRs in that it neither efficiently recruits β‐arrestins nor undergoes ligand‐induced internalization. Moreover, among the ACKR family, ACKR1 is unique in its ability to transport and display intact chemokines on the luminal surface of endothelial cells [12, 13]. Similarly, endothelial CCRL2 can present its ligand chemerin to circulating leukocytes expressing ChemerinR1 (CMKLR1) [14]. Through their ability to bind multiple chemokines, often with broad ligand promiscuity, and in some cases, non‐chemokine ligands, ACKRs play a central role in regulating the availability, distribution, and biological activity of chemoattractants within tissues (Tables 1 and 2)

TABLE 1.

Recognized ligands for the atypical receptors for chemoattractants.

Receptor	Chemokine families	Number of validated chemokine ligands	Non‐chemokine ligands	References
ACKR1	CC + CXC	22	LukE (S. aureus), HlgAB (S. aureus), DBP (P. vivax, P. knowlesi)	[69, 70, 71, 72, 73, 74, 75]
ACKR2	CC + CXC	19	gp120 (HIV), Staphopain A (S. aureus)	[76, 77, 78, 79, 80, 81, 82, 83, 84]
ACKR3	CXC	2	vCCL2 (HHV‐8), MIF, opioid peptides	[85, 86, 87, 88, 89, 90]
ACKR4	CC	5	None	[31, 91, 92, 93]
ACKR5	CC + CXC + XCL + CX3CL	42	Opioid peptides, apelin, PACAP, lipoproteins	[46, 47, 58, 94, 95]
CCRL2	None	0	Chemerin	[96, 97]

Note: List of validated ligands for the atypical receptors for chemoattractants divided for chemokine family and non‐chemokine targets.

Abbreviations: DPB: Duffy binding protein, HlgAB: gamma‐hemolysin component AB, LukE: leucotoxin LukE; P. knowlesi: Plasmodium knowlesi, P. vivax: Plasmodium vivax; S. aureus: Staphylococcus aureus.

TABLE 2.

Promiscuity and overlaps of recognized chemokines by the atypical chemokine receptor family members.

Chemokine	Chemokine receptor	ACKR	Reference
CXCL1	CXCR2	ACKR1 (H&M, +++), ACKR2 (M, +), ACKR5 (H, +)	[69, 76, 94]
CXCL2	CXCR2	ACKR1 (H&M, +++), ACKR2 (H, +), ACKR5 (H, ++)	[46, 70, 76, 95]
CXCL3	CXCR2	ACKR1 (H&M, +++), ACKR5 (H, ++)	[58, 69]
CXCL4	CXCR3, CCR1	ACKR5 (H, +++)	[94]
CXCL5	CXCR2	ACKR1 (H&M, +++), ACKR2 (H&M, +), ACKR5 (H, ++)	[47, 70, 76]
CXCL6	CXCR1, CXCR2	ACKR1 (H&M, +++), ACKR5 (H, +)	[58, 70]
CXCL7	CXCR1, CXCR2	ACKR5 (H, +)	[94]
CXCL8	CXCR1, CXCR2	ACKR1 (H&M, +++), ACKR5 (H, ++)	[69, 70, 94]
CXCL9	CXCR3	ACKR1 (H&M, +), ACKR5 (H&M, ++)	[46, 70, 95]
CXCL10	CXCR3	ACKR1 (H&M, +), ACKR2 (H&M, +), ACKR5 (H&M, +++)	[46, 69, 70, 77, 95]
CXCL11	CXCR3	ACKR1 (H&M, +++), ACKR2 (H&M, +), ACKR3 (H&M, +++), ACKR5 (H&M, +++)	[46, 70, 76, 85, 95]
CXCL12	CXCR4	ACKR1 (H&M, dimer, +++), ACKR2 (H&M, +), ACKR3 (H&M, +++), ACKR5 (H&M, +++)	[46, 71, 72, 76, 85, 95]
CXCL13	CXCR5	ACKR1 (H&M, +), ACKR5 (H&M, +++)	[70, 94]
CXCL14	CXCR4	ACKR5 (H&M, +++)	[94]
CXCL16	CXCR6	ACKR5 (H&M, +)	[46, 95]
CXCL17	GPR25	ACKR5 (H&M, +++)	[58]
CCL1	CCR8	ACKR1 (H&M, +), ACKR5 (H, +++)	[58, 70]
CCL2	CCR2	ACKR1 (H&M, +++), ACKR2 (H&M, +++), ACKR5 (H, +++)	[58, 69, 78]
CCL3	CCR1, CCR5	ACKR2 (H&M, +), ACKR5 (H +)	[58, 79]
CCL3L1	CCR1, CCR3, CCR5	ACKR2 (H, +++)	[78, 79]
CCL4	CCR5	ACKR2 (H&M, +++), ACKR5 (H, +++)	[58, 80]
CCL5	CCR1, CCR3, CCR5	ACKR1 (H&M, +++), ACKR2 (H&M, +++), ACKR5 (H, ++)	[46, 69, 70, 78, 79, 95]
CCL7	CCR1, CCR2, CCR3	ACKR1 (H&M, +++), ACKR2 (H&M, +++)	[70, 81]
CCL8	CCR1, CCR2, CCR3	ACKR1 (H&M, +), ACKR2 (H, +++), ACKR5 (H, ++)	[58, 70, 78, 79]
CCL11	CCR3, CCR5	ACKR1 (H&M, +++), ACKR2 (H&M, +++), ACKR5 (H&M, +)	[58, 78, 79]
CCL12	CCR2	ACKR2 (M, +++)	[78]
CCL13	CCR2, CCR3	ACKR1 (H&M, +++), ACKR2 (H, +++), ACKR5 (H, +++)	[47, 80, 82]
CCL14	CCR1, CCR3, CCR5	ACKR1 (H&M, +++), ACKR2 (H, +++), ACKR5 (H, +++)	[47, 80]
CCL15	CCR1, CCR3	ACKR5 (H, ++)	[94]
CCL16	CCR1, CCR2, CCR5, CCR8	ACKR1 (H&M, +++), ACKR5 (H, +++)	[70, 94]
CCL17	CCR4	ACKR1 (H&M, +++), ACKR2 (H&M, +++), ACKR5 (H&M, +)	[70, 83, 94]
CCL18	CCR8	ACKR1 (H&M, +), ACKR5 (H, +)	[70, 94]
CCL19	CCR7	ACKR4 (H&M, +++), ACKR5 (H, +++)	[31, 91, 94]
CCL20	CCR6	ACKR4 (H&M, ++), ACKR5 (H, ++)	[92, 93, 94]
CCL21	CCR7	ACKR4 (H&M, +++), ACKR5 (H, ++)	[31, 91, 95]
CCL22	CCR4	ACKR2 (H&M, +++), ACKR4 (H&M, ++), ACKR5 (H&M, ++)	[83, 92, 93, 94]
CCL23	CCR1	ACKR5 (M, ++)	[94]
CCL24	CCR3	ACKR5 (H&M, +++)	[94]
CCL25	CCR9	ACKR4 (H&M, +++), ACKR5 (H&M, +++)	[31, 91, 94]
CCL26	CCR3	ACKR5 (H, ++)	[94]
CCL27	CCR3	ACKR5 (H&M, +++)	[94]
CCL28	CCR10	ACKR5 (H&M, +++)	[94]
CX3CL1	CX3CR1	ACKR5 (H, +)	[94]
XCL1	XCR1	ACKR5 (H, ++)	[94]
XCL2	XCR1	ACKR5 (H, +)	[94]

Note: Promiscuity of atypical chemokine receptors summarized by the recognition of targeted chemokines. H: human; M: mouse. + weak, ++ medium and +++ strong ligand‐receptor interaction, respectively.

Through these functions, they contribute to the spatial organization of immune responses and the prevention of excessive leukocyte accumulation [2, 15, 16, 17, 18].

Within the lung, atypical chemoattractant receptors are expressed by specialized endothelial subsets and are increasingly recognized as key regulators of immune surveillance and inflammatory resolution [19, 20]. However, despite growing interest in their biology, their specific roles in the pulmonary vasculature and their contribution to disease remain incompletely understood.

In this review, we summarize current knowledge on the role of endothelial atypical receptors for chemoattractants in lung immune regulation, discuss their involvement in inflammatory and pathological conditions, and explore their potential as therapeutic targets.

1.1. The Role of ACKRs in Lung Inflammation

The lung, to ensure efficient gas exchange, is characterized by a highly vascularized alveolar compartment, composed of a specialized endothelial cell network. Similar to the alveolar epithelium, comprising alveolar type 1 (AT1) and type 2 (AT2) cells, the alveolar capillary endothelium is also heterogeneous and can be divided into aerocyte (aCap) and general capillary (gCap) ECs. aCaps are primarily optimized for gas exchange and immune cell recruitment, while the gCaps regulate vasomotor tone, antigen presentation, immunomodulation, and also serve as a reservoir of endothelial progenitor cells during tissue repair [21, 22, 23, 24].

Owing to its peculiar vascular structure, the lung employs distinct mechanisms for leukocyte extravasation. The alveolar capillary network represents the predominant endothelial surface of the lung and the principal site of neutrophil recruitment during acute alveolar inflammation. Of note, leukocyte recruitment in alveolar capillaries differs from the classical venular paradigm, relying largely on mechanical sequestration [25] and exhibiting variable dependence on selectins and β2 integrins depending on the inflammatory stimulus [26, 27]. In contrast, leukocyte recruitment in bronchial and peribronchial tissues largely follows the classical rolling, adhesion, and transmigration cascade occurring in postcapillary venules [8]. In addition, leukocyte transmigration has been reported in pulmonary arterioles under severe inflammatory conditions [28]. However, several important questions remain unresolved, including whether transmigration occurs predominantly via paracellular or transcellular routes, whether gCap and aCap endothelial cells differentially support transendothelial migration (TEM), also considering that aCaps constitutively express Icam1, whereas gCaps upregulate the expression of adhesion molecules only during inflammation [21, 26]. Similarly, the roles of junctional molecules (e.g., JAM family proteins) and endothelial glycocalyx glycosaminoglycans (GAGs) in regulating this process are still poorly understood. Nevertheless, both aCaps and gCaps contribute to immune cell extravasation, and their selective expression of atypical chemoattractant receptors may locally modulate chemotactic gradients and shape leukocyte recruitment. Following transmigration, leukocytes transiently localize within the thin interstitial space before crossing the epithelial layer to reach the alveolar space [6, 17, 25].

Continuous exposure to inhaled particles and pathogens places the lung in a dynamic balance between immune activation and homeostasis. To avoid excessive or chronic inflammation, lungs evolved complex immunoregulatory mechanisms that spatially confine immune responses. At steady state, the expression of ACKRs is tightly controlled in a cell type‐specific manner, as revealed by scRNA sequencing analysis of murine lung ECs [26] (Figure 1A,B). This spatial regulation of chemokines enables selective regulation of leukocyte subsets, thereby supporting rapid response to stressors and pathogens, while limiting tissue damage.

FIGURE 1.

The expression of atypical chemoattractant receptors in the lung vasculature at steady state or during acute inflammation. (A) Umap representing a scRNA‐seq dataset of mouse lung endothelial cells [26]. The data were downloaded from GSE148499 and explored with Seurat v5.2 [98]. (B) Dot plot presenting the normalized expression of atypical chemoattractant receptors in the lung endothelium at homeostasis. (C) Dot plot presenting the normalized expression of atypical chemoattractant receptors, divided by population, as a time course upon intraperitoneal LPS injection (for more details, please refer to Zhang et al. [26]).

During inflammation, atypical chemoattractant receptor expression is dynamically regulated. In a model of LPS‐induced systemic inflammation, both aCaps and gCaps in the lungs display time‐ and cell type–specific changes in the expression of Ackr2, Ackr3, Ackr5 (Gpr182) and Ccrl2 (Figure 1C) [26, 27]. In addition, Ackr1, expressed in the endothelial compartment, may contribute to chemokine gradient formation through transcytosis and display of chemokines on the endothelial surface [17, 24, 29]. Of note, only a few reports have documented Ackr4 expression in the lung endothelial compartment [30, 31]. Collectively, the coordinated and cell‐type‐specific expression of atypical chemoattractant receptors contributes to shaping the local inflammatory microenvironment and promoting resolution of inflammation (Figure 1C) [21, 26].

Due to the central role of lung ECs in immune regulation, their dysfunction is associated with multiple acute and chronic multifactorial diseases, including acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) [32]. However, the specific contribution of endothelial atypical chemoattractant receptors to these pathologies remains incompletely understood.

In patients and in pulmonary fibrosis models, ACKR1⁺ ECs are frequently observed in proximity to immune and alpha‐smooth muscle actin positive (αSMA⁺) mesenchymal cells forming niches that promote fibroblast activation and disease progression [33, 34]. Consistent with this, Ackr1‐ko mice are protected from neutrophil‐mediated lung injury, suggesting a pathogenic role linked to chemokine regulation [35, 36]. Data generated with full Ackr1‐ko mice should be interpreted with caution, as ACKR1 is expressed by both ECs and erythrocytes. Consequently, the relative contribution of endothelial cells versus erythrocyte ACKR1 cannot be readily distinguished. Nevertheless, ACKR1 expressed on erythrocytes is considered to act as a sink for chemokines, controlling chemokine plasma levels [13, 37], whereas ACKR1 on ECs can act as a scavenger, transcytosing them to the luminal surface, enhancing leukocyte migration [38]. In addition, in postcapillary venules, ACKR1 regulates chemokine availability by both degrading and transporting them from the abluminal to the luminal endothelial surface, where they can contribute to the recruitment of neutrophils and other immune cells [14].

ACKR2, expressed by lymphatic and aCap ECs (Figure 1B) [20, 39], functions as a scavenger receptor mainly for inflammatory CC chemokines and plays a key role in regulating leukocyte trafficking (Tables 1 and 2). In the lung, however, its role appears context‐dependent. In several models of inflammation, Ackr2 deficiency is associated with reduced tissue injury, decreased leukocyte infiltration, and improved lung function [40]. In general, altered chemokine availability influences the recruitment of CCR2⁺ and CCR5⁺ IFNγ‐producing γδ T cells and modulates the Th17 response, which is critical for fibrosis progression. Similarly, in influenza A virus infection, Ackr2 ko displays increased recruitment of CCR5⁺ lymphocytes, improved viral clearance, and reduced lung damage [41]. Additional evidence suggests that ACKR2 may also control T lymphocyte trafficking, highlighting a vascular compartment‐specific role in controlling immune cell entry into the lung [20]. These findings suggest that ACKR2, despite its canonical anti‐inflammatory function, may contribute to disease progression by reshaping chemokine gradients in specific contexts.

ACKR3 (CXCR7), expressed in both venous and capillary compartments (Figure 1) [42], also exhibits context‐dependent functions. In acute injury models, such as intratracheal injection of bleomycin or hydrochloric acid (HCl), ACKR3 retards fibrosis; its expression appears protective, limiting fibrosis progression. Whereas chronic injury leads to its downregulation and the emergence of a macrophage‐driven pro‐fibrotic environment [43]. In patients with interstitial pulmonary fibrosis, ACKR3 expression is reduced, further supporting its role in tissue homeostasis [43]. However, in LPS‐induced acute lung injury, ACKR3 antagonism improved lung recovery via increased serum levels of CXCL11 and CXCL12, highlighting the complexity of its function [44].

Evidence for other ACKRs remains limited. For example, ACKR4‐mediated scavenging of CCL21 has been implicated in regulating CCR7‐dependent dendritic cell (DC) trafficking, but data in the lung context are still scarce [30, 45]. Similarly, ACKR5, the most recently identified member of the ACKR family and characterized by a broad chemokine scavenging capacity (Tables 1 and 2) [10, 46], is expressed in vascular ECs of the lung (Figure 1) [47]; however, its role in lung inflammation responses has not yet been identified.

Overall, current evidence on the roles of ACKR expression in lung ECs remains limited. Further studies are required to define their contribution to immune surveillance and to evaluate their potential as therapeutic targets in pulmonary diseases.

1.2. ACKRs and CCRL2 in Lung Cancer and Immune Surveillance

Chemokines are known to regulate the composition of the immune tumor microenvironment (TME) [1, 5, 48]. Similar to inflammatory conditions, ACKRs expressed by lung endothelial and stromal cells within the TME exert complex and context‐dependent functions by modulating chemokine gradients (Figure 2). Their tightly regulated expression can lead to divergent biological outcomes depending on tissue and disease stage. In primary tumors, ACKRs are often associated with protective effects, largely due to their ability to shape chemokine gradients and limit the recruitment of immunosuppressive myeloid populations [37, 49, 50]. However, this paradigm does not fully extend to metastatic sites such as the lung. In this organ, endothelial ACKR expression, physiologically involved in maintaining tissue homeostasis, may instead facilitate metastatic seeding and growth.

FIGURE 2.

The role of atypical chemoattractant receptors in modulating cancer immune responses. ACKR1 expression by lung endothelial cells can promote infiltration of cytotoxic lymphocytes, supporting antitumor immunity. Conversely, in premetastatic niches, endothelial ACKR1 promotes neutrophil recruitment and metastatic colonization by regulating chemokine availability through transendothelial chemokine transport and presentation. ACKR2 in primary tumors is protective as it limits the accumulation of pro‐tumoral myeloid cells by reducing chemokine‐driven inflammation. Meanwhile, in metastatic niches, ACKR2 activity has been linked to tumor progression. ACKR3 expression enhances tumoral vascular permeability, tumor cell extravasation, and the establishment of a supportive metastatic niche by modulating the CXCL12/CXCR4 axis; ACKR4 expression promotes lung metastasis mainly by modulating NK cell–dependent responses. ACKR5 expression in lymphatic endothelial cells from melanoma models indicates that it has pro‐tumoral roles by restricting T cell infiltration. CCRL2 expressed by gCap or inflammatory aCaps acts as a chemerin‐presenting molecule by presenting chemerin to innate immune cells positive for the conventional chemerin receptor ChemerinR1.

ACKR1 exemplifies this duality. In primary tumors, endothelial ACKR1 expression correlates with increased infiltration of cytotoxic T lymphocytes, thereby supporting antitumor immunity [51]. In contrast, within the lung premetastatic niche, tumor‐derived factors induce ACKR1 upregulation on ECs, promoting neutrophil recruitment and creating a permissive environment for metastatic colonization [52].

ACKR2 similarly displays a context‐dependent role. In primary tumors, ACKR2 limits the accumulation of pro‐tumoral myeloid cells by dampening chemokine‐driven inflammation [53]. Conversely, in metastatic settings, including melanoma and breast cancer, ACKR2 activity has been associated with tumor progression [54, 55]. Mechanistically, its chemokine‐scavenging function may reduce the recruitment of effector T cells in the lung. Consistent with this, endothelial‐selective deletion of ACKR2 enhances T cell infiltration and activation, ultimately restricting metastatic outgrowth [20].

ACKR3 adds further complexity due to its dual function as both a scavenger receptor and an activator molecule via β‐arrestin‐dependent intracellular pathways that still need extensive characterization [37]. Nonetheless, in the lung endothelium, ACKR3 is upregulated in response to tumor‐derived signals and promotes metastasis [48]. Here, the predominant effect of ACKR3 is the scavenging of CXCL12, thereby reshaping gradients mediated by the CXCL12/CXCR4 axis that regulate tumor cell retention at primary sites, endothelial activation, and leukocyte trafficking. Through these combined effects, ACKR3 may enhance vascular permeability, tumor cell extravasation, and the establishment of a supportive metastatic niche. Although ACKR3 efficiently scavenges both CXCL12 and CXCL11, the biological consequences of CXCL11 scavenging remain largely unexplored. While extensive evidence demonstrates that ACKR3 regulates tumor progression and inflammation through modulation of the CXCL12/CXCR4 axis, whether ACKR3 limits CXCR3‐dependent recruitment of effector CD8⁺ T cells, Th1 cells, and NK cells by scavenging CXCL11 has received remarkably little experimental attention [56].

ACKR4, a scavenger of CC chemokines (Tables 1 and 2), also plays a critical role in immune cell positioning. In the lung, stromal ACKR4 expression promotes metastasis across multiple tumor types, including B16 melanoma, 3LL lung carcinoma, and RM1 prostate carcinoma [57]. ACKR4 alters chemokine availability within the tissue, thereby affecting the localization and function of immune cells. By modulating the availability of the CCR7 ligand CCL21, the genetic deletion of ACKR4 enhances the recruitment and activation of CD103+ DCs and CD8+ T cells resulting in improved anti‐tumor immunity [57]. This highlights the importance of chemokine gradient regulation in controlling immune surveillance.

Although data on ACKR5 in lung ECs during cancer progression remain limited, evidence from melanoma models indicates that ACKR5 expression in lymphatic endothelial cells restricts T cell infiltration. Genetic deletion of Ackr5 increases intratumoral CXCL9 and CXCL10 levels, enhancing CXCR3‐dependent T cell recruitment and promoting antitumor immunity, including improved responsiveness to immune checkpoint blockade and adoptive cell therapies [58].

Beyond ACKRs, other atypical receptors for chemoattractants also contribute to immune regulation in the lung tumor microenvironment. CCRL2, expressed by gCaps, regulates Natural Killer (NK) cell migration by binding and presenting chemerin to ChemerinR1⁺ NK cells. Upon inflammation, Ccrl2 expression can also be induced in aCaps (Figure 1B) [19]. CCRL2 deficiency impairs NK cell recruitment and activation, weakening early lung antitumor immune surveillance [19, 59].

Overall, although current evidence remains limited, the spatial and temporal regulation of ACKRs by lung ECs emerges as a critical determinant of effective antitumor immunity. Targeting these receptors to modulate chemokine availability represents a promising strategy to enhance T‐cell‐mediated responses and reshape the tumor microenvironment. Conversely, strategies aimed at increasing CCRL2 expression may support the recruitment of ChemerinR1⁺ NK cells to the lung and further strengthen immune surveillance [19].

This complex and dynamic landscape opens new therapeutic perspectives, which will be briefly discussed in the following section.

1.3. Therapeutic Targeting of atypical Receptors for Chemoattractants in Lung Cancer

The expression of ACKRs by lung ECs is influenced by the inflammatory status of the tissue, where their expression is associated with the regulation of specific leukocyte subsets. This makes ACKRs attractive candidates for therapeutic intervention, particularly in immunologically “cold” tumors and chronic inflammatory diseases. By fine‐tuning local chemokine levels without directly activating canonical chemokine receptor signaling, ACKRs represent promising pharmacological targets [60, 61] (Figure 3).

FIGURE 3.

Therapeutic interventions to modulate the atypical chemoattractant receptor expression or function. As CCRL2 expression by the tumor is severely downregulated, treatment with the de‐methylating agent 5‐aza‐2′‐deoxycytidine can restore Ccrl2 protein levels in the lung endothelium, thus promoting lung recruitment of antitumoral ChemerinR1+ NK. ACKR3 acts as a chemokine sink that can modulate the CXCL12/CXCR4 axis, thereby influencing local leukocyte trafficking. The small molecule ACT‐1004‐1239, by blocking ACKR3 binding to CXCL12, can alter the immune cell composition of the lung, thus ameliorating the fibrotic response.

Recent work on CCRL2 highlights this potential. CCRL2 expression in lung ECs supports efficient NK homing, yet in human lung cancer it is often downregulated through epigenetic mechanisms [19]. Pharmacological reversal of this repression using hypomethylating agents such as decitabine restores CCRL2 expression, enhances the recruitment of ChemerinR1⁺ NK cells to the lung, and improves tumor control in preclinical models [19]. These findings suggest that modulation of CCRL2 expression may represent a viable strategy to reshape innate immune infiltration and reprogram the tumor microenvironment.

In contrast, direct therapeutic targeting of ACKRs in cancer remains largely unexplored. Limited evidence suggests that ACKR2 expression can be downregulated through activation of the oncogenic signaling pathways, such as the K‐Ras‐B‐Raf‐ERK pathway in Kaposi sarcoma, leading to altered monocyte‐derived macrophage recruitment and polarization toward a pro‐tumoral M2‐like phenotype [62].

More substantial evidence comes from nonmalignant lung diseases, where small molecules targeting ACKR3 have shown therapeutic potential. ACKR3 agonism is a promising approach to attenuate fibrotic processes, although its effects are modest and variable, suggesting that combination approaches may be required [63]. Small molecules, such as ACT‐1004‐1239, reduce lung vascular permeability and leukocyte infiltration in models of acute lung inflammation [44], while the agonist TC14012 limits epithelial damage and fibrosis by modulating profibrotic signaling pathways [43].

Overall, although therapeutic strategies targeting ACKRs are still in their early stages, emerging evidence supports their potential to modulate immune responses and improve disease outcomes in both inflammatory and oncological settings.

1.4. Future Perspectives

Overall, the role of atypical chemoattractant receptor expression by ECs in lung immunosurveillance remains incompletely understood, as only a limited number of studies are currently available. A key priority for future research is to better define the spatiotemporal regulation of atypical chemoattractant receptors within the lung vasculature, both in homeostasis and disease, to clarify their contribution to inflammatory responses and their resolution. A major challenge in the field is the limited availability and application of genetic tools that enable selective manipulation of ACKRs in defined endothelial subsets. Recent studies have described conditional mouse models targeting either gCaps or aCaps endothelial cells [21, 64]. However, these models require further validation and characterization before they can be broadly adopted. Nevertheless, the development and application of lung EC‐specific conditional mouse lines, combined with conditional ACKR knockout models, will be instrumental in defining the specific roles of endothelial ACKRs in lung inflammation, fibrosis, and cancer.

In parallel, the possibility of genetically or pharmacologically modulating atypical chemoattractant receptor expression represents an attractive therapeutic avenue. By controlling local chemokine availability, it may be feasible to selectively influence the recruitment and retention of specific immune populations, such as NK or T cells, thereby reshaping the lung immune microenvironment and enhancing protective responses.

Another important aspect that remains largely unexplored is the impact of genetic variants of atypical chemoattractant receptors. Although some variants have been shown to affect chemokine scavenging and receptor interactions [65, 66, 67], their functional relevance to lung endothelial cell pathology is still poorly understood. Similarly, the role of atypical chemoattractant receptors in chemokine and other chemoattractant receptor heterodimerization and biased signaling warrants further investigation in the context of lung EC physiopathology.

Targeting ACKRs in combination with established therapies may offer additional clinical benefits. Modulation of chemokine gradients could potentially improve the responses to immune checkpoint blockade, which currently benefits only a subset of lung cancer patients [68], and may also complement antifibrotic strategies in chronic lung diseases.

Finally, despite the peculiar mechanism of trans‐endothelial migration within the alveolar vasculature, very little is known about its dynamics. Future studies should be devoted to evaluating if trans‐endothelial migration mainly involves a paracellular route, a transcellular route, or both, as well as clarifying the role of both aCap and gCap under homeostatic and inflammatory conditions.

Altogether, a more refined understanding of endothelial cell specialization and compartmentalized atypical chemoattractant receptor expression will be essential to fully elucidate their role in lung immune regulation and to guide the development of novel therapeutic approaches.

Author Contributions

M.L., M. Thelen, R.B., and S.S. conceived and wrote the manuscript. E.B., F.S., and M. Turchetti contributed to manuscript preparation. G.S. and A.D.P. critically evaluated the manuscript and contributed to the preparation.

Artificial Intelligence Generated Content

No artificial intelligence‐generated content was utilized.

Conflicts of Interest

All authors declare no conflicts of interest.

Data Availability Statement

The authors have nothing to report.