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Lin, L.; Hu, K. tPA and NF-kB Signaling in Renal Inflammation. Encyclopedia. Available online: https://encyclopedia.pub/entry/47082 (accessed on 17 April 2024).
Lin L, Hu K. tPA and NF-kB Signaling in Renal Inflammation. Encyclopedia. Available at: https://encyclopedia.pub/entry/47082. Accessed April 17, 2024.
Lin, Ling, Kebin Hu. "tPA and NF-kB Signaling in Renal Inflammation" Encyclopedia, https://encyclopedia.pub/entry/47082 (accessed April 17, 2024).
Lin, L., & Hu, K. (2023, July 20). tPA and NF-kB Signaling in Renal Inflammation. In Encyclopedia. https://encyclopedia.pub/entry/47082
Lin, Ling and Kebin Hu. "tPA and NF-kB Signaling in Renal Inflammation." Encyclopedia. Web. 20 July, 2023.
tPA and NF-kB Signaling in Renal Inflammation
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Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of blood coagulation, fibrinolysis, and matrix degradation, and has been shown to act as a cytokine to trigger various receptor-mediated intracellular signal pathways, modulating macrophage function in response to kidney injury. 

tissue plasminogen activator (tPA) macrophage function signal transduction inflammation nuclear factor- κB (NF-κB) low-density lipoprotein receptor-related protein (LRP-1) annexin A2 macrophage polarization

1. Introduction

Macrophages, as a critical component of innate immunity, play a fundamental role in immune defense against pathogens, as well as in the modulation of inflammatory responses. In general, macrophages within various tissues and organs are differentiated from bone marrow myeloid progenitor-derived monocytes in the circulation and undergo a closely regulated process of adaption to the local microenvironment [1]. However, mounting evidences have shown that macrophages are also derived from embryonic yolk sac and fetal liver and become a part of the local resident cell population participating in organ-specific functions [2].
Macrophages are not homogenous and consist of variably mixed populations in various organs, such as liver Kupffer cells and brain microglial cells, that carry out local microenvironment-specific functions [3]. Under various physiological or pathological conditions, macrophages acquire distinct functional phenotypes through polarization that are generally categorized into two subsets as either classically activated (M1) or alternatively activated (M2). In general, M1 macrophages garner high motility and promote inflammation and damage through a combination of transcription factors such as NF-κB, whereas M2 macrophages help to resolve inflammation and promote tissue remodeling [4]. Of note, M1 and M2 only represent two extremities of a full spectrum of macrophage polarization, and most differentiated macrophages fall into various states of polarization between M1 and M2. Additionally, macrophage polarization is a dynamic process, and phenotypic switch between M1 and M2 happens under various pathological conditions [5].
One of the histological hallmarks of chronic kidney disease (CKD) is renal infiltration and accumulation of inflammatory cells, such as macrophages. Macrophage infiltration and accumulation has been shown to correlate with the severity of kidney damage in human patients with chronic kidney disease [6][7].

2. tPA Structure and Dual Functions of Protease and Cytokine

Tissue plasminogen activator (tPA), a 69 kDa glycoprotein consisting of 527 or 530 amino acids, is a member of the serine protease family that plays a pivotal role in the homeostasis of blood coagulation and fibrinolysis, as well as matrix regulation [8]. tPA is synthesized within cells and released as a single-chain enzyme, which is subsequently cleaved by plasmin into a two-chain form that consists of a heavy chain and a light chain. The single-chain tPA contains four domains: (i) a finger (F) domain, which is homologous to the first domain of the fibronectin; (ii) an EGF domain, which is homologous to EGF; (iii) two Kringle (K) domains; and (iv) the catalytic protease (P) domain. The heavy chain of the two-chain tPA contains F, EGF, and K domains, while the light chain contains the P domain. The F domain is essential for the binding of tPA to fibrin and interactions with tPA-associated receptors, such as low-density lipoprotein receptor-related protein (LRP-1) and annexin A2. The EGF domain allows tPA to interact with EGF receptors. The Kringle domains contain active sites with an affinity for lysine in mediating protein–protein interaction. The P domain of tPA consists of Histidine 322, Asparagine 371, and Serine 478 [9], which are critical to the protease functions of tPA. The single mutation of these sites, such as Serine 478 to Alanine, renders tPA catalytical inactivation, while its other functions remain intact [10]. This mutant non-enzymatic tPA plays an instrumental role in identifying the protease-independent effects of tPA.
As a serine protease, tPA and its cousin serine protease urokinase plasminogen activator (uPA) cleave plasminogen into biologically active plasmin, which degrades insoluble fibrin fibers and initiates the fibrinolytic process. Additionally, tPA also regulates the degradation of extracellular matrix (ECM) through plasmin-activated matrix metalloproteinases (MMPs) [8][11]. Besides its protease activities, the researchers and others, using the above-mentioned non-enzymatic tPA, have shown that tPA acts as a cytokine triggering multiple signal pathways to regulate various cellular processes [12][13][14][15][16] and is involved in the pathogenesis of numerous disease models, including liver fibrosis, ischemic brain injury, and chronic kidney disease [8][11][17][18].

3. Renal Origin and Distribution of tPA after Kidney Injury

tPA is produced and released by vascular endothelial cells in the circulation to maintain blood flow through anticoagulation and fibrinolysis. Within endothelial cells, tPA is stored in Weibel–Palade bodies, which also store von Willebrand factor, an important player in blood coagulation cascade [19]. A variety of stimuli, such as vascular endothelial growth factor, fluid shear stress, and thrombin, induce tPA mRNA expression in endothelial cells [20].
The normal renal expression of tPA mRNA and protein is very low and usually hard to detect [21][22]. However, tPA mRNA is detected by in situ hybridization analysis in glomerular endothelial cells, podocytes, and the epithelial cells of the distal collecting ducts [21]. tPA mRNA expression is induced in the damaged proximal tubules after acute kidney injury (AKI) [21]. In a unilateral ureter obstruction (UUO)-induced CKD model, both tPA mRNA and protein levels are dramatically induced in the renal interstitium [13][14][22]. Interstitial parenchymal cells, such as fibroblasts, as well as infiltrated inflammatory cells in the diseased kidney, such as macrophages, may also contribute to the interstitial induction of tPA [23]. Intriguingly, the previous work has demonstrated that myeloid cells are the primary source of obstructive injury-induced tPA responsible for renal fibrogenesis and inflammation [24]. Specifically, the researchers have generated chimeric mice that lack tPA in either myeloid cells or renal parenchyma by bone marrow transplantation between tPA wildtype (WT) and knockout (KO) mice (bone marrow donor/recipient: WT/WT, WT/KO, KO/WT, and KO/KO) followed by UUO challenge. Notably, it has been found that WT/WT and WT/KO mice (myeloid cells with WT tPA) display similar and dramatically increased renal fibrosis and macrophage accumulation, whereas KO/WT and KO/KO mice (tPA-deficient myeloid cells) show similar but significantly reduced fibrosis and macrophage infiltration. Additionally, tPA in the circulation has little effect on the renal accumulation of macrophages and fibrosis. Thus, myeloid cells are the main source of renal endogenous tPA responsible for obstructive injury-induced macrophage accumulation and renal fibrosis.

4. Renal Receptors of tPA Signaling

tPA does not have a dedicated or specific receptor. However, tPA is known to bind to cell surface LRP-1 and annexin A2. Mature LRP-1 is a 600 kDa transmembrane protein first identified as a tPA receptor in hepatocytes [25]. LRP-1 consists of an extracellular 515 kDa α subunit and an 85 kDa β subunit. The LRP-1 α subunit consists of an extracellular segment comprising domains I, II, II, and IV, while the β subunit contains a transmembrane domain and a cytosolic tail harboring two NPxY motifs and numerous tyrosine residues [26][27][28][29] (Figure 1). tPA has been shown to bind domains II and IV in the α subunit and can induce the phosphorylation of tyrosine site(s) in the β subunit [15][26][30]. Phosphorylation of the tyrosine residue(s) is essential for LRP-1 to relay its signal, of which Tyr4507 phosphorylation mediates tPA-induced renal fibroblast proliferation through activation of its downstream, the extracellular signal-regulated kinase 1/2 (Erk1/2) and the p90 ribosomal S6 kinase (p90RSK) pathway [15]. It remains unknown how exactly the binding of tPA to LRP-1 induces phosphorylation of LRP-1 tyrosine residue(s) and subsequent activation of downstream signal mediators. Tyrosine residues on the β subunit of LRP-1 are known to provide docking sites for signaling adaptor proteins, including Shc [31][32][33], which upon phosphorylation will then recruit Grb2-Sos and activate Ras signaling [33]. Tyr4507 phosphorylation induced by v-Src has been found to cause the association of LRP-1 and Shc [31][34]. Thus, Shc likely mediates tPA/LRP-1-induced Ras-Erk1/2 signaling. tPA and LRP-1 mediates multiple signaling cascades and influences various cellular processes, including ECM remodeling, myofibroblast activation, and fibroblast accumulation and proliferation, as well as macrophage survival and peritoneal macrophage efflux [13][14][15].
Figure 1. Structure of LRP-1. LRP-1 has an extracellular α subunit containing tPA-binding II and IV domains and an intracellular β subunit with two NPxY motifs and several tyrosine residues that can be phosphorylated to initiate signal transduction. * stands for phosphorylation.
Another recognized but less known receptor for tPA is annexin A2, a member of the calcium-regulated phospholipid-binding protein which is widely expressed in various types of cells and tissues [35]. Annexin A2 was first discovered as a tPA receptor in the microglia of the central nervous system (CNS) [36]. Structurally, annexin A2 is a 36 kDa protein containing three regions: the core region, the C terminal, and the N terminal (Figure 2). The unique structure of annexin A2 allows it to dock onto cell membranes in a peripheral and reversible manner [37]. There are four highly α-helical annexin repeats within the core domain in the C terminus of annexin A2. These α-helical annexin repeats mediate the binding of annexin A2 to the cell membrane [37]. tPA has been shown to bind to the hexapeptide LCKLSL (residues 7–12) in the N terminus of annexin A2 [38]. However, unlike LRP-1, annexin A2, as a membrane-associated protein, lacks the transmembrane domain and can only dock onto the cell surface [37][39]. Therefore, it is presumable that annexin A2 requires additional co-receptors for its intracellular signal relay [37]. The previous work has shown that integrin CD11b is one of these co-receptors, which mediates the relay of these signals triggered by the binding of tPA to annexin A2 [16]. Past studies have demonstrated the binding of tPA to annexin A2 on the surface of various cells, including macrophages, endothelial cells, and some cancer cells [16][40][41][42]. Binding of tPA to annexin A2 has been shown to play an important role in modulating ECM homeostasis, promoting cell migration, and activating microglia [36][42][43].
Figure 2. Structure of annexin A2. Annexin A2 has no transmembrane domain and docks onto the cell surface through its four highly α-helical annexin repeats in the C terminus. tPA binds to the hexapeptide LCKLSL in the N terminus.

5. tPA and NF-kB Signaling in Renal Inflammation

Activation of NF-κB is a central signaling event in inflammation onset and progression. The NF-κB family consists of five members: p50, p52, p65 (RelA), RelB, and c-Rel, which form a variety of homo- and hetero-dimers [44][45]. The most common heterodimer is p50/p65, which is detectable in most cell types [46]. NF-κB family members have a common conserved Rel homology domain (RHD). The RHD is a 300-amino-acid-long region that functions as the NF-κB site for homo-/hetero-dimerization, nuclear translocation, and DNA promoter binding [46][47]. However, only p65 (RelA), RelB, and c-Rel contain the carboxy-terminal transactivation domain (TAD) which is required for transcriptional activation [46]. In an inactive state, NF-κB is sequestered in the cytoplasm by specific members of the inhibitory κB (IκB) family. The IκB proteins possess ankyrin repeat motifs interacting with the RHD of NF-κB members, which effectively inhibits and sequesters NF-κB out of the nuclei [46]. Upon activation, IκB is phosphorylated and degraded, leading to the release and nuclear translocation of p65/p50 or c-Rel/p50 (canonical activation) or RelB/p52 (non-canonical activation), and subsequently NF-κB-dependent gene transcription [44][45].
The canonical pathway is triggered by a variety of signals, such as proinflammatory cytokines and pathogen-associated molecular patterns (PAMPs), which activate cell surface receptors, including pattern-recognition receptors (PRRs), Toll-like receptors (TLR), and T-cell receptors (TCR), leading to the phosphorylation and degradation of IκB and subsequently nuclear translocation of p65/p50 or c-Rel/p50. In contrast, the non-canonical pathway responds to a more specific set of stimuli. Although there are other receptors, tumor necrosis factor (TNF) cytokines and their respective TNF receptors (TNFR) are the most well-known receptors that mediate the non-canonical NF-κB pathway. These involved TNFRs include lymphotoxin-β receptor (LTβR), B-cell-activating factor receptor (BAFFR), fibroblast growth factor-inducible factor 14 (Fn14), and others [48]. After stimulation of TNFs and pertinent receptors, NF-κB inducing kinase (NIK) is activated to initiate the non-canonical pathway, leading to nuclear translocation of RelB/p52 [44][45].
Both NF-κB and tPA have been implicated in the modulation of renal inflammation and fibrosis. NF-κB has been shown to be associated with immune-related kidney diseases, including lupus nephritis and IgA nephropathy [49][50]. NF-κB activation has also been documented in animal models of both acute and chronic kidney diseases [45][51][52]. The extent of NF-κB activation usually correlates with the severity of kidney fibrosis [53]. Additionally, NF-κB inhibition has been shown to reduce inflammatory responses and fibrosis in various CKD models, further validating the significant role of NF-κB in kidney diseases [54][55].

The researchers have hypothesized that tPA promotes renal inflammation through modulating NF-κB pathway based on the previous findings of the concurrent induction of tPA and activation of NF-κB during the progression of CKD and the competency of tPA in regulating renal inflammatory responses [29]. The researchers have investigated the role of tPA and NF-κB in a mouse UUO model of CKD and have found that tPA promotes kidney fibrosis and inflammation. After obstructive injury, tPA knockout mice have displayed less collagen deposition, fewer CD11b-positive macrophage infiltration, and reduced activation of NF-kB in the diseased kidneys, as indicated by lower renal p65 phosphorylation and less NF-kB-dependent chemokines. The researchers have further demonstrated that tPA activates NF-κB signaling independent of its protease activity via the canonical pathway in macrophages by inducing IκB phosphorylation and triggering the nuclear translocation of p65/RelA, and subsequently transcription of NF-kB-dependent chemokines such as interferon-γ-inducible protein (IP)-10 and macrophage inflammatory protein (MIP)-1 α [16]. Intriguingly, LRP-1 as the most-studied receptor of tPA does not mediate tPA-activated NF-κB signaling, because siRNA knockdown of LRP-1 has had little effects. Instead, annexin A2 has been shown to mediate tPA’s effects. Because cell surface annexin A2 lacks the transmembrane domain and can only dock onto cell membrane in a peripheral manner [37], the researchers have proposed that annexin A2 may function as a coreceptor of a known outside-in signal transduction pathway, such as the integrin signaling. It’s known that tPA binds to integrin Mac-1 (CD11b/CD18) in macrophages [23], the researchers have investigated the possible interaction between annexin A2 and CD11b. It has been discovered that tPA promotes the aggregation of annexin A2 and CD11b in macrophages, and such interaction is also induced in the obstruction-injured kidney. Further in vitro studies have defined that tPA-induced aggregation of annexin A2 and CD11b activates its immediate downstream effector integrin-linked kinase (ILK), which, in turn, leads to phosphorylation and degradation of IκB, release and nuclear translocation of NF-κB dimers, and subsequently DNA binding and transcription of target proinflammatory genes [16]. These findings have defined a novel signaling mechanism of tPA-mediated NF-κB activation in promoting macrophage infiltration and renal inflammation. It’s worth mentioning that macrophages also produce tPA which may activate NF-κB signaling in macrophages in an autocrine manner initiating a vicious cycle of amplification.

Of note, it should be pointed out that the effect of tPA on NF-κB signaling is context dependent and affected by many factors, such as cell types, cellular states, and organ specificities. One of the notable examples is that tPA has been shown to suppress NF-κB activation in LPS-stimulated macrophages through LRP-1-mediated miR-155 [56]. The anti-inflammatory activity of tPA is mediated through the interaction of LRP-1 and its coreceptor N-methyl-D-aspartate Receptor (NMDA-R), which is characterized as a neuron ionotropic glutamate receptor in neurons, macrophages and Schwann cells [56][57]. LRP-1/NMDA-R-mediated effect is cellular state-dependent [58]. Non-stimulated mouse peritoneal macrophages express very low levels of the NMDA-R and are not responsive to tPA. However, after treatment with colony-stimulating factor-1 (CSF-1), activated macrophages display increased cell-surface NMDA-R and responsiveness to tPA [59]. Moreover, Zhang et al. has demonstrated that tPA and LRP-1 mediates cerebral ischemia-induced NF-κB activation [18]. They have found that ischemic insult-induced NF-κB activation is attenuated after LRP inhibition or tPA knockout [18]. Therefore, tPA may execute cell type-specific biological functions by binding to different membrane receptors (LRP-1 or annexin A2) or their coreceptor, such as NMDA-R and CD11b, and initiating different intracellular signaling events to modulate NF-κB activation [16][18][56].

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