The four members of the β2 integrin family, which are surface expressed only on leukocytes, have critical functions within the innate and adaptive immune systems (1, 2). Various β2 integrin nomenclatures exist, resulting in each member having multiple designations: CD11a/CD18 (α_Lβ₂, LFA-1, alphaLbeta2), CD11b/CD18 (α_Mβ₂, Mac-1, CR3, alphaMbeta2), CD11c/CD18 (α_Xβ₂, p150.95, CR4, alphaXbeta2) and CD11d/CD18 (α_Dβ₂, alphaDbeta2) (1, 2). For the following review, the CD11/CD18 nomenclature will be used exclusively. Acting as adhesion receptors, β2 integrins induce leukocyte adhesion and transmit bidirectional signals (1). Inside-out signalling describes signalling molecules binding to the cytoplasmic tail and inducing a change in integrin conformation. Outside-in signalling describes ligand binding to the extracellular I domain and transmission of a signal into the cytoplasm (3). The collection of adhesive and signalling mechanisms form the functionality of β2 integrins in leukocyte trafficking, cytokine release, phagocytosis, toll like receptor (TLR) signalling, B cell receptor (BCR) signalling, immunological synapse signalling, and targeted cell killing (1).

CD11d/CD18 is an understudied member of the β2 integrin family. First characterized in canines in 1995 (4), CD11d is now understood to be expressed by a variety of human leukocytes (5, 6) and to have both adhesion and signalling functions (7, 8). This review aims to examine known CD11d structure, expression, functionality, associated pathophysiological states, and targeted immunomodulatory agents. A focus of CD11d study has been its role in leukocyte migration, retention, and its contribution to the harmful accumulation of leukocytes in various pathophysiological states. Currently, two separate groups are developing CD11d-targeted agents to modulate the harmful recruitment of leukocytes following acute neurotrauma (9–12) and during chronic inflammatory disease (13). Less is known regarding the CD11d protein structure and bidirectional signalling pathways that have been determined for the other known β2 integrins. Sequence comparisons, predicted structures, and predicted functionalities will be presented alongside the known β2 integrin counterparts to analyse these lesser-known aspects of CD11d biology.

Each β2 integrin is a heterodimeric type I transmembrane protein composed of a variable alpha chain (CD11a-d) and a common beta chain (CD18). The two chains dimerize non-covalently and each consists of several extracellular domains, a singular transmembrane domain, and a short cytoplasmic tail (14) (Figure 1). The conformation and clustering of integrins heavily regulate their ligand avidity and functionality on the cellular membrane (21, 22). Multiple factors impact integrin conformation and clustering including inside-out signalling, outside-in signalling and thermodynamic equilibriums (21, 23, 24). Four conserved conformations have been observed across CD11a-c that are labelled: bent-closed, bent-open, extended-closed, and extended-open (Figure 1) (15, 16, 21, 22, 25, 26). The bent-closed conformation has a low ligand affinity and is regarded as inactive. Stimulatory signals can activate the integrin resulting in the extension of the extracellular domains into an extended-closed conformation before the transition to the fully activated extended-open conformation. The fourth conformation, bent-open, may allow for an alternative transition pathway to the extended-open conformation (25, 26). The bent-open conformation is stabilized by the binding of cis ligands – a ligand that is present on the surface of the β2 integrin expressing leukocyte (18–20). The detailed processes involved in integrin activation are beyond the scope of this review and we refer the reader to the following articles (16, 21, 27). In leukocytes under basal conditions, β2 integrins predominately favour an inactive bent-closed conformation that binds ligands with low affinity (1, 16).

The gene encoding CD11d, ITGAD, is located downstream of the ITGAM (CD11b) and ITGAX (CD11c) genes on chromosome 16 (28–30). All three genes are encoded in the same direction and clustered separately from ITGAL (CD11a), which is also located on chromosome 16 (31). Phylogenetic analysis echoes these observations with CD11a diverging from a common CD11b-d ancestor (32). The encoded CD11d amino acid sequence shares the greatest homology with CD11c (70%), followed by CD11b (59%), while much less homology is shared with CD11a (32%) (33). Each known CD11 chain has a short and long isoform due to alternative splicing (28–31). The CD11d short isoform differs from the long isoform by the absence of a glutamine at residue 500 (30). No study has directly investigated the potential differences between these two CD11d isoforms. Inclusion and exclusion of the signal peptide in the residue numbering of the CD11 chain varies between separate studies. For consistency this review will position residues along the respective long CD11 isoform and numbering will include the signal peptide sequence.

Mouse models are commonly used to study CD11d because of the presence of a murine ortholog to each known β2 integrin. The positioning of all four murine β2 integrin orthologs echoes the pattern observed in humans. Murine Itgad, Itgax, and Itgam are encoded in the same direction and clustered separately from Itgal on chromosome 7 (34–37). Targeted deletion has created CD11d^-/- mice that lack a functional copy of the Itgad gene. CD11d^-/- mice display normal growth, development, fertility, IgG serum levels, peripheral leukocytes counts, and no increase in spontaneous infection (38, 39). The weight of murine CD11d^-/- spleens was noted to be heavier than wildtype spleens at weeks 10-11 but no difference was recorded at weeks 17-18 (38).

The human ITGAD gene is under unique transcriptional regulation compared to the other β2 integrins (40, 41). Sp1 and Sp3 are shared transcription factors involved in the regulation of the CD11a-d and CD18 promoters (40). Sp1 is expressed equally across all leukocytes and induces the basal expression of CD11d. Meanwhile, Sp3 alters Sp1 basal expression with cell-type specific repressor and activator functions (42). Divergent to CD11a-c, transforming growth factor-β-inducible early gene-1 (TIEG1) and two isoforms of gut-enriched Kruppel-like factor 4 (GKLF/GKLFa) interplay with Sp1 to regulate CD11d in a cell and stimulant-specific manner (40, 41). TIEG1, GKLF/GKLFa, and Sp1 bind to the CD11d promoter at a common binding site via zinc-finger DNA binding domains (40). TIEG1 contains three repression domains and represses CD11d expression in non-myeloid cells; however, in differentiated myeloid cells an increase in TIEG1 binding is coupled with CD11d upregulation (41). The reported role of TIEG1 in CD11d activation is novel and the exact mechanism of cell-specific CD11d activation remains unclear. A leading hypothesis states that the competition or interaction between TIEG1 and a set of transcription factors may sum to form the observed activation of CD11d in differentiated myeloid cells (41). The complete set of CD11d transcription factors responsible for these cell-specific responses is unknown. One known transcription factor that does compete with TIEG1 to bind the CD11d promoter and likely impacts CD11d expression is GKLF/GKLFa. Histone deacetylase 1 and 2 associate with GKLF/GKLFa bound to the CD11d promoter to repress CD11d expression across myeloid, non-myeloid, and differentiated myeloid cells (40). Sp1, TIEG1, and GKLF/GKLFa all contribute to the bimodal CD11d response to phorbol myristate acetate (PMA) stimulation observed in myeloid cell lines. Acute 24-hour 10nM PMA stimulation decreases Sp1 binding, maintains GKLF/GKLFa binding, and decreases CD11d mRNA expression. Prolonged 48-hour 100nM PMA stimulation, representing myeloid differentiation, corresponds with the release of GKLF/GKLFa, resurgence of Sp1, increase in TIEG1, and CD11d mRNA upregulation (40, 41).

A putative transcription factor also involved in CD11d regulation is proliferator-activated receptor-γ (PPAR-γ). Mice deficient in PPAR-γ have splenic red pulp macrophages with substantially downregulated CD11d mRNA while CD11a and CD11b mRNA are upregulated (43). Furthermore, sequence analysis identifies several potential binding sites for PPAR-γ within the CD11d promoter (43). PPAR-γ is a member of the nuclear hormone receptor superfamily and is expressed in a range of leukocytes including monocytes/macrophages, neutrophils, lymphocytes, and dendritic cells (44). The confirmation of PPAR-γ binding to the CD11d promoter and its direct impacts on CD11d regulation have yet to be reported. A separate study has also postulated a set of CD11d transcription factors that are involved in myeloid cell differentiation. Oxidized and acetylated low-density lipoproteins (Ox-LDL and Ac-LDL) induce the upregulation of CD11d mRNA during HL60 foam cell formation, but do not impact CD11d mRNA expression in foam cells (45). Foamy macrophages are known to be involved in atherosclerosis and drive plaque formation (46). Additionally, chronic spinal cord injury pathophysiology presents foamy macrophages within the injury lesion (47). A potential candidate for this unknown transcription factor involved in foam cell formation and CD11d expression is PPAR-γ (43). PPAR-γ binds to Ox-LDL, is expressed within monocytes/macrophages, and is involved in foam cell formation (44, 48, 49). Further investigation is warranted to characterize PPAR-γ as a putative CD11d transcription factor and its possible connection to CD11d upregulation in response to Ox-LDL during foam cell formation.

Certain conserved motifs heavily regulate the tertiary structure of the CD11 chain and mediate the known conformational changes. The open and closed integrin conformations refer to the state of the α-I domain regulated by a metal ion-dependant adhesion site (MIDAS) and socket for isoleucine (SILEN) (50) (Figure 1). These two motifs can impact the position of the α7 helix to either stabilize the closed or open α-I domain state. Under basal conditions, the SILEN motif acts to stabilize the closed α-I domain conformation by interacting with an invariable isoleucine within the CD11 α7 helix (17) (Figure 2). Activation can shift the position of the α7 helix and open the α-I domain MIDAS motif for divalent metal ion binding (14, 16, 17). It is important to note that not all divalent metal ions have the same effect on the α-I domain conformation. In CD11b, Mg²⁺ binds the MIDAS motif to stabilize the open state, while Ca²⁺ binds the MIDAS motif to stabilize the closed state (58). Separation of the CD11 and CD18 cytosolic tails is another key conformational change during integrin activation. The conserved GFFKR or “hinge” motif maintains the association of the cytosolic tails during the inactive state (Figure 2). Deletions within the GFFKR sequence activates the integrin to a high affinity state (52). Interestingly, the conserved GFFKR +2 tyrosine in CD11b-d is postulated to be hidden within the membrane in the inactive conformation, while accessible for potential phosphorylation in the active conformation (57). The role of the conserved GFFKR +2 tyrosine has yet to be defined but it may play a part in outside-in signalling. Regarding the presence of these motifs within CD11d, a crystallized structure has yet to be elucidated thus the conservation of these structures within CD11d have not been confirmed. Conservation of key sequences, however, predict the existence of similar structures within CD11d (Figure 2). Alterations to the predicted CD11d α7 helix sequence can induce a constitutively active or inactive affinity state, thus supporting the conservation of the open and closed α-I domain conformations (51). Ultimately, structural studies are still required to confirm the presence of the bent-closed, bent-open, extended-closed, and extended-open conformations in CD11d/CD18.

Phosphorylation of the CD11 and CD18 cytoplasmic tails are key to the signalling mechanisms of β2 integrins. The cytoplasmic tails of CD11a-c are found to be constitutively phosphorylated whereas the cytoplasmic tail of CD18 is phosphorylated upon activation (59, 60). Notably in CD11a-c, a constitutively phosphorylated serine residue on the cytoplasmic tail is a required step for complete integrin activation (Figure 2). Deletion of these serine phosphorylation sites prevents complete activation and decreases ligand affinity (53–55). On the CD18 chain, phosphorylation of Thr⁷⁵⁸ during inside-out activation is a subsequent requirement for complete integrin activation. Deletion of the CD18 Thr⁷⁵⁸ phosphorylation site impairs adhesion and actin mobilization (61). No study has yet confirmed a homologous CD11d constitutively phosphorylated serine; however, three serine residues do exist in the CD11d cytoplasmic tail, as well as a putative CK2 phosphorylation site not observed in the other β2 integrins. The constructed CK2 consensus sequence (56) – S-X-X-D/E-X-pS-P – predicts CK2 phosphorylation at position S given prior phosphorylation at position pS. Thus, the putative CD11d CK2 phosphorylation site at Ser¹¹⁴⁸-Cys¹¹⁵⁴ predicts phosphorylation at Ser¹¹⁴⁸ given constitutive phosphorylation at Ser¹¹⁵³ (Figure 2). The importance of phosphorylating the alpha chain during outside-in signalling differs between integrin families. Alpha chain phosphorylation is involved with the respective outside-in signalling pathways of integrins α3Aβ1, α6Aβ1, and α6Aβ4 (62). In comparison, the involvement of alpha chain phosphorylation in β2 integrin outside-in signalling has yet to be demonstrated (62, 63). The unique presence of a putative CD11d CK2 phosphorylation site may translate to the involvement of alpha chain phosphorylation in CD11d/CD18 outside-in signalling.

The functions of CD11d/CD18 heavily revolve around the CD11d ligand binding specificity. β2 integrins are widely known to bind ligands via the α-I domain (64–66). Initial studies demonstrated the binding of human CD11d/CD18 to both human vascular cell adhesion molecule-1 (VCAM-1) and induced endothelial cell adhesion molecule-3 (ICAM-3) via the α-I domain (5, 67, 68). The binding affinity for VCAM-1 was found to be greater than that of ICAM-3 (68). Later work identified promiscuous binding to extracellular matrix (ECM) associated proteins including; fibrinogen, vitronectin, fibronectin, Cyr61, and plasminogen (51). Recently, CD11d has been described to bind the protein modification 2-(ω-carboxyethyl)-pyrrole (CEP), which is a by-product of lipid peroxidation (13, 69) (Figure 3). As a group, bent-open β2 integrins have been shown to bind sialylated FcγRIIA, ICAM-1, and ICAM-3 expressed on the same leukocyte (18–20). While CD11d has been shown to bind ICAM-3, there has yet to be direct evidence of CD11d binding ICAM-3 in a bent-open conformation.

Residues involved in the CD11d ligand binding site were first discovered through homolog studies with CD11b (51). Structural studies of CD11b determined that Lys²⁶¹-Arg²⁷⁷ diverges from CD11a, bestowing promiscuous ligand binding to the CD11b α-I domain. CD11d shares 60% amino acid sequence homology with the α-I domain of CD11b and a similar Lys²⁶¹-Lys²⁷⁷ sequence that is also important for promiscuous ligand binding (Figure 2). A CD11a/CD18 chimera containing the CD11d Lys²⁶¹-Lys²⁷⁷ sequence shares the CD11d/CD18 ligand binding specificity but with unique binding affinities (51). Additional residues, therefore, contribute to the complete CD11d binding site. Future structural studies are required to determine the structure of this CD11d ligand binding site and determine key residues.

The understanding of human CD11d expression has evolved over time with expression reported in select human myeloid and lymphoid cells. Initial investigations noted low expression of CD11d amongst peripheral blood leukocytes, moderate expression on myeloid cells, and strong expression on tissue-specialized myeloid cells including splenic red pulp macrophages and granulocytes, synovial macrophages, and foamy macrophages (5, 71). Key exceptions were moderate CD11d expression on peripheral eosinophils and an absence of CD11d on liver specialized Kupffer cells (5, 67). A later study further investigated the expression of CD11d on lymphoid cells and revealed strong expression on B cells and NK cells. Amongst T cells, γδ T cells express CD11d at consistently greater levels than αβ T cells, while Vδ1 surface expression on CD11d⁺ γδ T cells is more prevalent than Vδ2 (6) (Table 1).

Detection of CD11d expression does vary across species. Under basal conditions, CD11d expression is detected at low levels on murine peripheral blood leukocytes including neutrophils and monocytes (38, 76). One study has described that murine T cells lack CD11d surface expression, while a separate study has reported surface CD11d expression on γδ T cells and αβ T cells (39, 75). Both studies used flow cytometry. In canines, CD11d surface expression is extremely low on peripheral leukocytes, but is present on a small portion of CD8⁺ T cells (4). Tissue-specialized myeloid cells mainly conserve the pattern of expression across observed species. CD11d protein expression is consistently detected in human, canine, and mouse splenic red pulp macrophages; however, CD11d is consistently absent from liver Kupffer cells (4, 5, 38). IC-21 cells – a peritoneal macrophage cell line from C57BL/6 mice – express CD11d and have been used to model CD11d ligand binding interactions (51). Finally, investigation within a rat model demonstrated low CD11d surface expression amongst peripheral leukocytes and consistent expression amongst splenic macrophages (79). Rat alveolar macrophages also express low levels of CD11d protein (80) (Table 1).

Regulation of CD11d expression is cell-type specific and influenced by the temporal duration of leukocyte stimulation. These regulatory nuances have been modelled across a diverse set of cell lines: THP-1 (monocytic), HL60 (promyelocytic), IM-9 (B-cell), and Jurkat (T-cell) (40–42). In myeloid cell lines (THP-1 and HL60), acute 24-hour 10nM PMA exposure decreases CD11d mRNA, while prolonged 48-hour 100nM PMA exposure substantially increases CD11d mRNA (40, 41, 45). Further analysis is still required to determine if the observed increase in CD11d mRNA results in an increased CD11d/CD18 surface expression. In non-myeloid cells (IM-9 and Jurkat), northern blot analysis did not detect CD11d mRNA before or after PMA stimulation (41, 42). Progressing beyond cell lines, investigations of CD11d upregulation in various pathophysiological states have further characterized the regulation of this β2 integrin. CD11d upregulation has been observed in spinal cord injury (SCI) (74), atherosclerosis (78), obesity (81), arthritis (71), acute lung injury, and acute respiratory distress syndrome (ARDS) patients (7). In peripheral blood eosinophils isolated from the bronchi of allergic patients challenged with allergen, interleukin 5 was found to upregulate CD11d surface expression directly (67) (Table 2). An underlying constraint to all CD11d surface level expression is the co-expression with the CD18 β chain. Without the presence of CD18, CD11d is retained in the trans-Golgi network and is not functionally expressed on the cell surface (82).

β2 integrins have important outside-in signalling pathways induced by ligand binding. In general, integrins transduce outside-in signals from an active conformation; however, ligand binding to the inactive state can induce a conformational change and thereby transduce an outside-in signal (99). Antibody binding to the α-I domain in the presence of Mn²⁺ can also transmits outside-in signals as demonstrated in CD11b/CD18 (100). Canonical β2 integrin outside-in signalling pathways can impact cell motility, proliferation, survival, and cytokine expression. These detailed pathways are beyond the scope of this review and the reader can refer to the following reviews for in-depth analysis (2, 101). No outside-in signalling pathway has yet been elucidated for CD11d/CD18 but impacts of outside-in signalling have been described. Human monocytes incubated in wells coated with a variety of anti-CD11d murine monoclonal antibodies induced cell spreading along with the increased secretion of IL-8, IL-1β and MCP-1 (7). Human monocytes also secret IL-8 after binding human ICAM-3, but CD11d/CD18 is not the only integrin involved in binding ICAM-3 and transmitting an outside-in signal. Addition of a blocking anti-CD11d clone only partially reduces IL-8 secretion. CD11a/CD18 also recognizes ICAM-3 and could function redundantly to induce IL-8 secretion following ICAM-3 binding (7). A different signalling impact is detected for CD11d amongst human NK cells. Interactions between ICAM-3 on neutrophils and CD11d/CD18 on NK cells have been associated with IFN-γ release in co-cultures stimulated with LPS plus IL-15/IL-18 (73). Individually, NK cells also release IFN-γ following binding to immobilized ICAM-3 and IL-15/IL-18 stimulation. Application of a blocking anti-CD18 clone did abrogate NK cell IFN-γ release following ICAM-3 binding but could not differentiate between CD11d and CD11a signalling contributions (73). These studies highlight the presence of a CD11d/CD18 outside-in signalling cascade and the potential difficulties in separating the signalling contributions of individual integrins with shared ligand specificities. Future investigation is warranted to characterize the signalling molecules involved in the CD11d/CD18 outside-in signalling cascade. The distinct sequence variation in the CD11d cytoplasmic tail may indicate unique signalling pathways within the CD11d/CD18 outside-in signalling cascade not observed within the previously described canonical β2 integrin pathways.

β2 integrins as a family are known to participate in the phagocytosis of pathogens and senescent cells (102), but the role of CD11d in phagocytosis is largely undefined. The initial identification of CD11d expression on splenic red pulp macrophages linked their function with phagocytosis of spent and/or infected erythrocytes (5). In contrast to this original postulate, a study has demonstrated that CD11d/CD18 was not required for clearance of parasitized red blood cells in a murine malaria model (38). In CD11d^-/- mice, peritoneal macrophages have no defect in the internalization of latex beads and phagocytosis of Salmonella Typhimurium (103). Additionally, a separate study found murine CD11d^-/- neutrophils and macrophages have no defect in the phagocytosis of Escherichia Coli (76). The current evidence, therefore, does not support CD11d/CD18 as a required participant in phagocytosis.

Both CD11b/CD18 and CD11d/CD18 have been associated with the formation of multinucleated giant cells (MNGCs) formed from the fusion of differentiated macrophages (104). The role an integrin plays in the process of macrophage fusion is thought to be proportional to the density of the integrin. CD11d/CD18 is expressed in a lower density than CD11b/CD18 on macrophages and likely plays a lesser role in macrophage fusion (104).

CD11d expression during thymocyte development impacts the immunological synapse and T cell proliferation (39). Thymocyte expression of both CD11b and CD11d has been reported to peak at days 12-17 in neonatal mice. Following thymic maturation, individual CD11b^-/- and CD11d^-/- knockout mice have the most severe T cell proliferation defects in response to staphylococcal enterotoxin (SE). The transient CD11b/CD11d co-expression is hypothesised to be crucial to T cell development as either knockout develops T cells with reduced CD3, CD28, CD4 and CD8 expression (39). Interestingly, CD11d^-/- mice display normal T cell proliferation in an experimental autoimmune encephalomyelitis (EAE) model (105). EAE is designed to model the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) observed in multiple sclerosis (106). In this study susceptible CD11d^-/- mice were immunized with the MOG_35-55 peptide to induce EAE (105). The MOG_35-55 autoantigen induces a T cell MOG response, but no B cell MOG response (106). No difference in T cell proliferation was observed between susceptible CD11d^-/- and susceptible wildtype mice immunized with MOG_35-55 (105). A separate EAE study noted an increase in CD11a-d/CD18 integrin expression amongst γδ T cells, while no change was observed amongst αβ T cells (75). Notably, CD11d is the only β2 integrin whose deletion does not improve EAE (105). Further work is warranted to investigate these conflicting T cell proliferation results and reveal the underlying mechanisms of CD11d/CD18 in thymocyte development.

Currently, two therapeutic agents have been developed to target CD11d and modulate leukocyte migration during disease/injury development. A therapeutic anti-CD11d monoclonal antibody has been developed to block the infiltration of peripheral leukocytes into the CNS during acute neurotrauma and extensively studied within in vivo mouse and rat models (9–11, 114, 115, 120). A peptide inhibitor, P5 peptide, has also been developed to block CD11d-ligand interactions during macrophage mesenchymal migration (13). In vitro P5 peptide experiments demonstrated that the therapeutic was able to alter wildtype macrophage migration in a 3D matrix, while not impacting diapedesis. The therapeutic was then able to successfully transition into an in vivo model of prediabetic mice to prevent the accumulation of macrophages in WAT (13). P5 peptide therapy, therefore, is positioned to treat chronic inflammatory diseases where CD11d contributes to the harmful accumulation of macrophages. Understanding off-target effects in addition to CD11d ligand binding are important in ensuring therapeutic safety. Both therapeutic agents target the ligand-binding α-I domain of CD11d, which could initiate integrin activation and/or outside-in signalling. Preliminary experiments report that P5 peptide may lock CD11d/CD18 into an intermediate state and prevent integrin activation (13). Further studies are still required to confirm this impact of P5 peptide on the CD11d/CD18 structure. Similar structural experiments between anti-CD11d therapy and CD11d/CD18 have yet to be performed. Previously, therapeutic attempts that targeted β2 integrins were not successful in translating into the clinic due to pervasive off-targeted effects. Efalizumab is an anti-CD11a therapeutic designed for long-term administration to treat chronic plaque psoriasis (129). CD11a is consistently expressed on all leukocytes and the systemic blockage of CD11a/CD18 activity led to severe side effects. Efalizumab was eventually discontinued due to the reactivation of JC virus and the development of fatal progressive multifocal leukoencephalopathy (130, 131). Currently, anti-CD11d therapeutics are mainly being developed for short-term use in acute inflammatory settings. A deeper understanding of CD11d expression and the affinity to each CD11d/CD18 conformation will assist in elucidating the range of potential side effects from these focused CD11d-targeted therapeutics.

Integrins are an essential part of the immune system and the discovery of CD11d/CD18 expanded the breadth of the β2 integrin family. To date, however, CD11d/CD18 remains the least understood β2 integrin with major gaps in the knowledge of its structure and signalling pathways. Exciting discoveries have been made on the impact of CD11d/CD18 on leukocyte migration, retention, and coordination of a staged immune response. Emerging evidence demonstrates that differences in CD11d density may contribute to the differences in M1/M2 migration patterns, while CD11d specificity to CEP adducts from lipid peroxidation may contribute to the staging of neutrophil and monocyte/macrophage waves. CD11d-targeted therapeutic agents have been designed to modulate the localization of leukocytes during the progression of diseases or injuries. The dual impacts of CD11d/CD18 on cytokine release and localization of leukocytes, however, confound the therapeutic mechanism(s) of action that alter the inflammatory microenvironment. Ample opportunities exist to further the basic knowledge of CD11d/CD18 biology, which will propel the exciting developments of CD11d-targeted biological agents.

EB and GD contributed to the conception and outline of the review. EB wrote the first draft of the manuscript. GD, LW, and AB expanded sections of the manuscript. All authors contributed to manuscript revisions and have read and approved the submitted version.

Funding that supported the creation of this manuscript was from the Canadian Institutes of Health grant OPG-363209 and by a donation from the National Hockey League Players Association.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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