Background: Integrin β1, as a member of the adhesion molecule family, is widely distributed in many kinds of cells and participates in multiple biological functions of the nervous system, including cytoskeleton reorganization, axon growth, and inflammatory injury. Summary: After nervous system injury, integrin β1 expressed by microglia is mainly involved in promoting inflammatory damage; integrin β1 expressed by astrocytes plays an important role in axon regeneration; integrin β1 expressed by endothelial cells mainly participates in vascular remodeling. We concluded that the function of integrin β1 depends on the location of the receptor cells. The mechanism of integrin β1, which is involved in the inflammatory response of immune regulatory cells and affects the axonal regeneration of neuronal cells, is the key to explore the repair after nervous system injury. The development of drugs targeting integrin β1 is expected to bring a breakthrough in the treatment of nervous system injury. Key Messages: This paper expounds the important role of integrin β1 in neurons of the nervous system and emphasizes the central role of integrin β1 in regulating non-neuronal cells after nervous system damage.

© 2022 The Author(s). Published by S. Karger AG, Basel

Introduction

Integrin is a cell surface receptor in a family of adhesion molecules, which is widely distributed in multiple kinds of cells. It is a transmembrane glycoprotein and can integrate the extracellular and intracellular environmental information through interaction with the corresponding ligands outside the cell and signal molecules inside the cell, thus obtaining the name “integrin” [1, 2]. In addition to mediating the firm adhesion of cells to extracellular matrix (ECM), integrins have the ability to transmit bidirectional signals across cell membranes [3-6]. This ability is involved in the regulation of many biological functions such as wound healing, cell differentiation, migration, and proliferation [7]. This requires a conformational change in two integrin subunits, α and β [3-6]. Studies have shown that the addition of Mn2+ or a high-affinity ligand mimetic peptide results in a switch from blade-like opening to an extended structure, and this conformational change is called the “switchblade” model [8-10]. In this model, three conformational states of integrins were proposed: bending (inactive state), extension (active state, low affinity), and extension with an open head (active state, high affinity) [11-14]. Integrins can bind to a variety of ligands, including cell receptors, ECM proteins, soluble proteins in various body fluids, and microbial proteins and carbohydrates [15, 16]. Notably, the integrin family needs to bind the tripeptide motif Arg-Gly-Asp (RGD) to achieve cell adhesion and signal transduction. The specificity of integrin signaling depends on a variety of factors, including heterodimer subtypes, ECM organization, and ligand recognition.

The intracellular structures formed by integrins and cytoskeletal proteins are known as "focal adhesions" and “focal complexes.” Early steps of integrin signaling involve interactions with tyrosine kinases such as focal adhesion kinase (FAK), Src kinase, integrin-linked kinase (ILK), Abelson mouse leukemia virus oncogene homolog (ABL), cytoskeletal proteins such as talin and kindlin, and scaffold molecules such as P130CRK-associated substrate (P130Cas). In a typical integrin pathway, the active FAK/Src complex interacts with P130Cas and paroxetine to recruit creatine kinase (Crk) adapter molecules, leading to the activation of several downstream molecules, including the Ras-associated C3 botulinum toxin substrate 1 (Rac1), serine/threonine protein kinase PAK 1, and c-Jun N-terminal kinase (JNK). The FAK/Src complex may also recruit other adapter molecules to activate major signaling pathways such as PI3K, Rho GTPase, P38, ERK, and phospholipase γ (PLCG) pathway [17] (Fig. 1). Currently, mammalian integrins include 18 different α subunits (α1–α11, αD, αE, αL, αM, αV, αX, and αII) and 8 β subunits (β1–β8) that form 24 α/β pairs in a specific manner. Integrins are divided into four subfamilies based on their binding specificity for different ECM proteins [18, 19], namely, (i) collagen-binding integrins [20-22], (ii) laminin-binding integrins [21, 22], (iii) RGD-binding integrins [21, 23, 24], and (iv) others [25-27] (Table 1). The affinity of different integrins may be different even though they are expressed in the same cell. However, even with the same ligand, the affinity of different integrins varies. Integrin binds to most binding sites formed by external ligand α chain and β chain outside the cell, and many proteins bind to integrin cytoplasmic domain inside the cell, especially integrin β chain. Few cytoplasmic proteins appear to bind to that α chain cytoplasmic domain [28]. Thus, integrin β chain determines the main function of integrin. It should be emphasized that the deletion of β1 subunit affects most of the integrin heterodimer, and systemic knockout of β1 subunit leads to embryonic death [29]. The absence of integrin β1 in the brain leads to death shortly after birth [30]. These results all emphasize that integrin β1 heterodimers play a key role in many biological processes. Among the integrin β subunits β1–β8, β1 is the most widely distributed subunit and plays the most important role [31-33].

Table 1.

Members of integrin β1 family expressed in the nervous system

Fig. 1.

Simple signal pathway diagram of integrin β1. The intracellular signal transduction of integrin β1 mainly affects the related pathways to exert biological functions, including actin polymerization, phosphatidylinositol signaling system, PI3K-Akt signaling pathway, Wnt signaling pathway, and MAPK signaling pathway.

Effect of Integrin β1 in the Nervous System

In the central nervous system (CNS), integrins are expressed in a variety of cells including neurons, astrocytes, microglia, and oligodendrocytes [31, 34-36]. The function of integrins depends on the cellular localization of the receptor. Integrins play different key roles in the nervous system due to their location in different receptor cells. They are important for adhesion [37], differentiation [37, 38], proliferation [39, 40], migration [37, 38, 41], lamination [41, 42], axonal guidance [43, 44], and axonal outgrowth [45, 46]. It is well known that cells respond by integrins recognizing almost all components of the ECM. For example, the integrin-collagen interaction constitutes a strong mechanical link that is involved not only in cell signaling but also in cell adhesion, migration, and remodeling of the collagen matrix [47].

The collagen-related integrins expressed in neurons are α1β1 [48, 49], α2β1 [50-52], and αVβ8 [53, 54]. Neuronal collagen-related integrins have been shown to contribute to neurite growth on collagen in cell cultures [48-50, 53]. A variety of integrins are involved in the formation, maturation, and function of synaptic connections [55-58]. For example, postsynaptic α5β1 plays an irreplaceable role in the spinal morphogenesis and synapse formation in hippocampal neurons through Src kinase, Rac, and G protein-coupled receptor kinase interacting protein 1 (GIT1) [59]. However, presynaptic β1 integrin acts as a postsynaptic intercellular adhesion molecule-5 (ICAM-5). This cross-synaptic interaction promotes filament extension and delays spinal maturation by preventing the shedding of the metalloproteinase-dependent ICAM-5 domain [60]. Various forms of synaptic plasticity in mature synapses are also regulated by integrins. Specifically, integrin synergistically regulates the intrinsic excitability of the synapse through interaction with ion channels (including Ca2+ and K+ channels) [61-63], and integrin β1 is related to the stability of long-term potentiation [43, 64-67].

The role of integrin family in axonal regeneration of neuronal cells has been excellently summarized in some review articles [68, 69]. The synergistic effect of integrin and ECM on synaptic plasticity and memory is of great significance in the brain. The role of integrin in brain has been reviewed by some scholars [57], as well as in neuropsychiatric diseases [70]. Apart from that, integrin β1 receptors are expressed not only in astrocytes but also in microglia [71]. Integrin β1 receptors can also interact with collagen and other ECMs, such as laminin and fibronectin [19].

Microglia and astrocytes can respond quickly and sensitively to the changes in the microenvironment of the nervous system. They play an important role in the immune response, maintaining homeostasis and regulating synaptic plasticity. The signaling mechanism of integrin on astrocytes has been well reviewed [72, 73]. This paper focuses on the signal transduction mechanism of integrin on microglia and reviews the role of integrin β1 in the inflammatory response and nerve regeneration after nervous system injury.

Integrin β1 and Nervous System Injury RepairIntegrin β1 and Inflammation

Integrin β1 is widely expressed in the nervous system and has a central role in physiological events [74]. Moreover, abnormal expression of integrin β1 is related to neuropathic pain, inflammation, and malignant diseases in the peripheral nervous system [75]. Studies have shown that mRNAs encoding integrin β1 are upregulated in dorsal root ganglion (DRG) neurons after sciatic nerve injury [76]. Integrin β1 and integrin β1-associated phosphorylated-FAK are upregulated in the spinal cord of chronic constriction injury rats [77]. Studies have shown that integrin β1 is activated by phosphorylation after binding to ECM proteins (especially collagen) [78-80]. In the context of neuroinflammation, ECM components can drive processes including, but not limited to, leukocyte infiltration of the CNS and activation of various immune cells [81]. Integrin β1 is a known phagocytic receptor that promotes the innate response of macrophages [82]. For instance, the interaction between fibronectin and integrin β1 in macrophages promotes the toll-like receptor 2/4 (TLR2/TLR4) signaling pathway to enhance the expression of pro-inflammatory mediators and the phagocytosis of macrophages [83]. The integrin β1/FAK signaling pathway in adipocytes is involved in promoting M1 macrophage polarization and ER stress-induced inflammatory response [84].

Besides, integrin β1 on microglia and astrocytes also plays a key role in the inflammatory response. It is well known that microglia are the resident immune cells and the most sensitive responders to CNS injury, with low activation thresholds. Cytotoxic mediators and endogenous proteins released by damaged neurons can stimulate resting microglia activation [85]. The expression of integrin β and MHC molecules on microglia is regulated by the presence of both pro-inflammatory and anti-inflammatory cytokines in the microenvironment [86]. One study pointed out that anti-integrin β1 antibody administration can inhibit microglia inflammatory response after spinal cord injury (SCI), inhibit chronic inflammation in glial scars, and improve the pathological microenvironment in the chronic phase after SCI [87]. This study also indicates that reactive astrocytes (RAs) can promote microglia inflammatory response through the fibronectin/integrin β1 pathway in glial scar after SCI [87]. Studies have long pointed out that fibronectin in the spinal cord can activate microglia through integrin β1 receptor and make them develop toward pro-inflammatory polarization [88]. In the hippocampus of rat brain, integrin β1 participates in the interaction of microglia and astrocytes and affects and mediates the extension of microglia branch trees to pro-inflammatory triggers [89]. Additional studies have shown an association between the localization of integrin β1 at the MPJ-APJ (microglia-to-astrocytes) contact point and the dynamic remodeling of microglia branch trees, which are present in the normal CNS and may enhance during inflammation [90]. To sum up, integrin β1 is not only the key for the normal function of neuronal cells but also plays an important role for non-neuronal cells in regulating the response to inflammatory injury in the nervous system.

The integrins, and in particular the integrin β1 family, play a role not only in nociceptor sensitization by inflammatory mediators [91-93] but also in regulating mechanical damage and post-injury neuronal excitability [94, 95]. For example, blocking the expression of α2β1 integrin at peripheral nerve endings has been shown to reduce the responsiveness of skin mechanical receptors to skin stretching [52, 94]. Integrin β1 is also involved in the pain mechanism of axonal substance P-induced mechanical damage to the spinal facet joint capsule ligament [96]. Besides that, integrin β1 has long been shown to play a role in the pain-induced PKC signaling pathway in primary afferent nociceptors [92], and recent data indicate that neuronal processing of nociceptive sensation can be affected by cell-ECM adhesion mediated by integrin β1 [97]. The overstretched ligament load can activate integrin β1 at the interface between the afferent nerve and its surrounding collagen and produce a mechanical sensory response, causing changes in electrophysiological signals and regulation of neurotransmitters [31, 94, 95]. Hyperalgesia induced by epinephrine and prostaglandin E(2) requires full integrin function, and integrin β1 plays a key role in inflammatory pain by interacting with components that mediate a second messenger cascade of inflammatory hyperalgesia [31, 92, 98].

Notably, some scholars have proposed that the integrins β1 mainly expressed in microglia are α4β1 and α5β1 [35], and the effects of these two fibronectin-related integrins α4β1 and α5β1 on nervous system injury have been reported. Anti-α4β1 monoclonal antibody can reduce inflammatory reaction and peroxidation, thus reducing the damage degree of notochord and exerting neuroprotective effect [99]. Similarly, the use of an inhibitor of α5β1 integrin, ATN-161, reduces infarct size, edema, infiltration of immune cells into the brain, and functional defects and is neuroprotective in the transient middle cerebral artery occlusion mice [100]. Therefore, the molecular mechanism of related interventions may be related to the mechanism of the integrin β1 signaling pathway in microglia. However, due to limited research reports, the expression of other types of integrin β1 in microglia remains unclear.

What is more, there are other molecules that can be involved in the effects of nervous system damage by binding to β1 integrin. For example, the RGD domain of osteopontin (OPN) interacts with integrin β1. OPN is an anti-inflammatory cytokine inducer and pleiotropic protein, which is weakly expressed in the brain under normal conditions but strongly expressed in microglia and astrocytes, and plays a neuroprotective role after brain injury [101]. In the Parkinson’s disease model, OPN plays a neuroprotective role by increasing the levels of glial and brain-derived neurotrophic factors with the help of integrin β1, accompanied by a decrease in the number of activated microglia but no change in the number of astrocytes [102]. In the damaged cerebral cortex after stabbing and in primary astrocyte cultures containing an inflammation inducer LPS, RAs also express OPN, and OPN plays a neuroprotective role in vivo and in vitro through the mediation of integrin α9β1 [103, 104]. Additionally, overexpression of integrin β1 reduces the sensory neuron toxic damage in a paclitaxel-induced peripheral sensory neuropathy model [105]. These studies suggest that integrin β1 in immune regulatory cells is mainly involved in the promotion of inflammatory injury, and neuronal cell integrin β1 is mainly involved in the related mechanisms of cell self-protection. This further illustrated that the function of integrin β1 depends on the cellular localization of the receptor.

Integrin β1 and Nerve Regeneration after Injury

Nerve regeneration refers to the regeneration and repair of damaged nerve tissue, including axonal elongation, germination, and growth of new axons, or myelin regeneration of nerve cells [106]. Integrin β1 has long been considered as a means to promote axonal regeneration and has recently been used to promote sensory regeneration of the spinal cord after injury to the central branch of DRG axons. For example, the endosomes with positive expression of integrin family molecules and their transporters Rab11 can limit the axonal availability of growth-promoting molecules [107, 108] and also can regenerate mature axons of the CNS after injury in vitro [109, 110]. Integrin can promote peripheral nervous system regeneration, but it cannot promote axonal regeneration in mature CNS. The reason for this includes axon localization: integrin is limited to cell bodies and dendrites and cannot be transported to adult CNS axons to play a role [108]. Integrin β1 can bind to tenascin-C, which is one of the components of glial scar tissue and is also an activator of integrin, to promote distant sensory axonal regeneration in the spinal cord [111]. It should be mentioned that the role of glial scars formed by astrocytes along widely damaged tissues in nerve regeneration [112] is controversial. Anderson et al. [113] pointed out that astrocyte scar formation contributed to axonal regeneration [113, 114]. However, Silver et al. [115] suggested that astrocytic scars directly inhibit axonal regeneration [115-119].

Astrocytes are not immune cells but play a key role in the neuroinflammatory injury pathway [120, 121]. Interestingly, although intact astrocyte scars strongly inhibit regeneration after CNS injury and lead to deterioration of functional recovery [115, 122, 123], RAs play a beneficial role in local immune regulation, neuroprotection, and tissue repair during the subacute phase of SCI [124-126]. According to some previous studies, in the subacute phase of SCI, the isolation of inflammatory cells infiltrated in the center of the lesion by RAs protects the nerves and promotes spontaneous motor recovery [120, 127]. Astrocytes express various integrins, among which, β1-integrins include α1β1, α2β1, α10β1, and α11β1 [128, 129], and regulate cell function by interacting with collagen-1 [31]. A study pointed out that the activities of the integrin β1 signaling pathway and Wnt/β-catenin pathway are important for the polarization of RAs after SCI in vitro and in mice with SCI [130]. The research by Hara et al. [131] has proved that the interaction between astrocyte integrin β1 receptor and collagen is the trigger factor for glial scar formation. The administration of anti-integrin β1 antibody during the subacute SCI can weaken astrocyte scar formation, enhance axonal regeneration ability, and improve nervous system function. It can be seen that integrin β1 participates in the mechanism of axonal regeneration after nervous system injury. In particular, integrin β1 in RAs plays a key role in promoting axonal regeneration in glial scars.

Moreover, some matrix components can also bind to integrin β1 to play a specific role. Nogo-A, a myelin-derived axonal rejection molecule, limits axonal regeneration after CNS injury. Nogo-A has been proved to inhibit integrin signal through the inactivation of integrin in vitro [132, 133] and in vivo [134]. Nogo-A can interfere with the functions of fibronectin-related integrins α4β1 and α5β1 but does not interfere with the functions of laminin-related integrin α6β1 in cell lines [132]. In vitro, the attenuation of DRG neurite growth by Nogo-A was consistently greater at fibronectin than at laminin [132]. A study found that myelin-associated glycoprotein (MAG, another myelin-derived axonal rejection molecule) was a direct receptor for integrin β1 and resulted in increased phosphorylation of FAK related to axonal growth [135]. Synergistic effects of kindlin-1 and α9β1 have also been shown to achieve the longest axonal regeneration observed in DRG [111, 136]. Moreover, some studies have shown that the overexpression of α9β1 integrin in DRGs does stimulate axonal regeneration [111, 136, 137]. Tenascin-C (TN-C) is one of the ECM glycoproteins of the CNS and participates in the development of the CNS. Its expression is upregulated after the brain injury or SCI [138, 139]. It is also known that TN-C has an immunomodulatory effect in neurodegenerative diseases and is highly correlated with astrocyte activation and glial scar formation [140]. Although TN-C inhibits mature axons, it promotes axon growth and regeneration when specifically bound to integrin α9β1 [141].

Integrin β1 and Revascularization after Nervous System Injury

Another important aspect of the repair of nervous system damage is vascular regeneration. The development and reconstruction of blood vessels require numerous regulatory factors that act on perivascular cells and endothelial cells. These regulatory factors can work with integrin β1 and play an important role in the angiogenesis process. Integrin β1 has been shown to contribute to thrombospondin-1/integrin/YAP signaling pathway-mediated angiogenesis and vascular remodeling [142, 143]. The latest study has also pointed out that integrin β1 is involved in the mechanism of TIMP1 in regulating the integrity of the endothelial barrier, playing a role in protecting the blood-brain barrier [144]. In particular, integrin α5β1 is upregulated as a fibronectin receptor in angiogenic endothelial cells in the CNS [145]. The direct binding of integrin α5β1 to Ang-1 enhanced the migration of endothelial cells. The in vivo and in vitro experiments showed that the activation of α5β1 integrin enhanced its interaction with Tie-2, making Tie-2 phosphorylated under the action of low concentration of Ang-1 and prolonging the action time of RTK, increasing kinase activity [146]. Ang-1 and its RTK are important participants in the formation of normal structures, differentiation, and maturation of new blood vessels. Stimulation of integrin α5β1 or controlled use of mild hypoxia may provide a new pathway for promoting angiogenesis of spinal cord blood vessels and improving vascular integrity [147]. Furthermore, a certain study has proved that integrin α5β1 plays an important role in driving endothelial proliferation and CNS angiogenesis [148]. The cross-over study of integrin signals showed that integrin αvβ3 could regulate the persistent migration of cells by inhibiting the downstream Rho kinase signaling of integrin α5β1 [149]. This indicated that β3 integrin inhibited the activation of β1 integrin. However, increased angiogenesis was found in a tumor study in β3-integrin-deficient mice [150], probably due to the loss of integrin β1 inhibition from integrin β3.

Summary and Views

There is increasing evidence that integrin β1 plays an important role in the occurrence and development of inflammatory and autoimmune diseases. In the progression of nervous system injury, the expression pattern of integrin β1 is changed, resulting in changes in the phenotype of neurons, astrocytes, and microglia. In the normal nervous system, integrin β1 on neuronal cells is involved in the development and growth of neurons as well as the regulation of synaptic function. However, in the process of nervous system injury and repair, integrin β1 not only participates in the promotion of inflammatory injury but also plays an important role in the axonal regeneration. Considering that integrin β1 signaling may have opposite functions according to subunit pairing and the type of immune cells it expresses, it is not surprising that these receptors play important roles in both promoting and negatively regulating inflammatory processes. Therefore, it is reasonable to believe that the integrin β1 signaling pathway is the key to balance the inflammatory response and axonal regeneration after nervous system injury.

Integrin β1 and its related signals are an integral pathway affecting nerve regeneration, angiogenesis, inflammatory responses, and peroxidation damage after nervous system injury. The integrin signaling pathway involves many molecules, which have a very wide range of participation and complex effect. For example, cAMP and growth factors, which can enhance the regeneration of signaling molecules under certain conditions, also affect the expression and function of integrin [151, 152]. The joint activation of the cAMP and integrin β1 signaling pathway has a significant negative effect on growth cone movement [153, 154]. Due to these complex interactions, the specific states of neurons and their surrounding environments are generally considered to be the key to determining whether regeneration-promoting strategies have positive, neutral, or even negative effects on neurite outgrowth. Even under a specific environment, integrin β1 promotes the regeneration and extension of damaged neurons and glial cells, but integrin β1-mediated transformation of quiescent astrocytes into RAs and excessive proliferation of glial cells will lead to the formation of glial scars, which is not conducive to nerve regeneration at scars and post-injury repair. In addition, the integrin β1-mediated adhesion has two sides. While leading important repair “elements” such as vascular endothelial cells and neurons into the injury area for repair, it also mediates the entry of inflammatory cells such as granulocytes and monocytes/macrophages, leading to serious inflammatory reactions and peroxidation damage.

In view of the multiple roles of integrin in the repair of nerve injury and the multilateral cooperation between spine surgeons, neurologists, intensive care physicians, and trauma specialists that may be required for the diagnosis and treatment of nervous system injury, clinicians should carefully consider the specific environment of its application and comprehensively estimate the possible consequences when using members of the integrin β1 family as targets for drug repair of nerve injury. Integrin and its downstream signaling pathways are associated with a number of pathological conditions, and a variety of antagonists against the integrin signaling pathway have been developed. Given the multifaceted and significant function of integrins in the brain, these receptors may also represent important therapeutic targets for specific neurological diseases. In the future, more clinical studies are needed to judge the applicability of integrin β1 extrapolation from animal models to humans in revealing the pathogenesis of nervous system injury, as well as the accuracy in evaluating the severity and prognosis of nervous system injury.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the Science and Technology Project of Nantong City (JC2020013) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_3107).

Author Contributions

Lei Yan was responsible for the literature search and discussion. Zhiming Cui revised the manuscript critically for important intellectual content and approved the final version.

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