TSG-6 (Tumor necrosis factor-alpha-stimulated gene/protein-6): An emerging remedy for renal inflammation

Abstract

The inflammatory response is a major pathological feature in most kidney diseases and often evokes compensatory mechanisms. Recent evidence suggests that tumor necrosis factor-alpha-stimulated gene/protein-6 (TSG-6) plays a pivotal role in anti-inflammation in various renal diseases, including immune-mediated and non-immune-mediated renal diseases. TSG-6 has a diverse repertoire of anti-inflammatory functions: it potentiates antiplasmin activity of inter-alpha-inhibitor (IαI) by binding to its light chain, crosslinks hyaluronan (HA) to promote its binding to cell surface receptor CD44 and thereby regulate the migration and adhesion of lymphocytes, inhibits chemokine-stimulated trans-endothelial migration of neutrophils by directly interacting with the glycosaminoglycan binding site of CXC motif chemokine ligand (CXCL)-8, and upregulates cyclooxygenase (COX)-2 to produce anti-inflammatory metabolites. Hopefully, further developments can target this anti-inflammatory molecule to the kidney and harness its remedial properties. This review provides an overview of the emerging role of TSG-6 in blunting renal inflammation.

Inflammation in kidney diseases

Kidney diseases can be classified as immune-mediated and non-immune-mediated, both of which may involve inflammatory processes. Immune-mediated renal disease occurs when the immune system directly targets specific antigens within the kidney (e.g., anti-glomerular basement membrane disease),¹ or when circulating immune complexes deposit in the kidney (as in lupus nephritis),² resulting in complement cascade activation, inflammatory cell infiltration, damage to endothelial cells, podocytes, and tubular cells, and ultimately kidney fibrosis.^{3, 4} On the other hand, inflammation also plays a pivotal role in kidney diseases initiated by non-immunological mechanisms (e.g., acute kidney injury [AKI] or toxic nephropathy). Damaged renal parenchymal cells and resident immune cells release cytokines to recruit circulating immune cells, which in turn release pro-inflammatory cytokines like interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 that favor a T-cell response, which exerts deleterious effects on the kidney in the acute phase of injury.^{5, 6}

Although the kidney has a remarkable capability to repair,⁷ renal damage may progress into chronic kidney disease (CKD) if severe or persistent injury and inflammation elicit insufficient or maladaptive repair.⁸ Inflammation during the repair phase is critically managed by anti-inflammatory cytokines. For instance, macrophages polarize to anti-inflammatory M2 phenotype to release anti-inflammatory cytokines that inhibit immune responses.⁹ In addition, regulatory T-cells can directly or indirectly target T-cells and B-cells to play an immunosuppressive role.¹⁰ Furthermore, IL-10, arguably the most potent anti-inflammatory cytokine, acts on both the innate and adaptive arms of the immune system, inhibiting production of pro-inflammatory cytokines and antigen presentation.^{11, 12} Similarly, interleukin-1 receptor antagonist (IL-1Ra), transforming growth factor-beta1 (TGF-β1), and growth differentiation factor (GDF)-15 are all important players in suppressing renal inflammation^13–15. Yet anti-inflammatory functions may also eventuate in kidney fibrosis, whereby CKD manifests as an excessive accumulation of extracellular matrix (ECM), resulting in renal dysfunction and disruption of normal architecture.¹⁶ Therefore, anti-inflammatory repair mechanisms need to be fine-tuned to achieve the required level of damage repair without unwarranted scarring. This balance might be achieved through carefully orchestrated activation of different types of anti-inflammatory mechanisms.

Within the anti-inflammatory cytokine pool, TNF-α-stimulated gene/protein-6 (TSG-6) is an emerging factor, which is increasingly linked to inflammation inhibition and injury repair.¹⁷ Extensive data on the potential therapeutic benefits of TSG-6 has accumulated from basic science experiments, offering valuable opportunities for its application in the treatment of human disease. This article aims to provide an overview of the involvement of TSG-6 in renal diseases, with a focus on its anti-inflammatory and anti-fibrotic functions.

Characteristics and anti-inflammatory mechanisms of TSG-6

TSG-6 was first discovered in 1990 when Lee et al. screened the λ-cDNA expression library of TNF-α-stimulated human diploid FS-4 fibroblasts.¹⁸ The human TNF-alpha-induced protein-6 (TNFAIP6, gene ID: 7130; aliases: TSG-6) gene is located on chromosome 2q23.3 and encodes a 35kDa polypeptide of 277 amino acids, the TSG-6 protein,¹⁹ which consists of an N-terminal segment, contiguous Link and CUB modules, and a C-terminal region (Figure 1).²⁰ The Link module, consisting of two helices (α1 and α2) and two antiparallel β-sheets, interacts with glycosaminoglycans like hyaluronan (HA) and chondroitin sulfate, as well as with matrix proteins,^{17, 21} while the CUB domain is involved in developmental processes.²²

Figure 1.

TSG-6 in kidney disease. Following an acute injury, TECs release pro-inflammatory cytokines (e.g., IL-1β, TNF-α) to activate resident macrophages, which also secrete pro-inflammatory cytokines to trigger inflammation cascades. These cytokines drive leukocyte migration and infiltration into the kidney. In addition, pro-inflammatory cytokines activate smooth muscle cells, TECs, and MSCs to produce anti-inflammatory cytokines like TSG-6. TSG-6 interacts with CD44 on M1 macrophages by forming a complex with HA, which dissociates CD44 from TLR, thereby limiting TLR-driven NF-κB signaling and decreasing the release of pro-inflammatory cytokines. TSG-6 also induces polarization of macrophages from a pro-inflammatory (M1) to an immunosuppressive (M2) phenotype, which produces some anti-inflammatory cytokines, like IL-10. Furthermore, TSG-6 mediates the transfer of heavy chains from IαI to HA, which stabilizes the ECM by cross-linking HA, while TSG-6 binding to bikunin potentiates its antiplasmin activity. In a persistent inflammatory environment, TGF-β1 induces EMT and activates myofibroblasts, which produce excessive ECM to promote renal fibrosis. TSG-6 decreases α-SMA, collagen-I, and fibronectin expression in TECs to attenuate EMT, and suppresses plasmin activation and thereby TGF-β1 activation. TSG-6, tumor necrosis factor-alpha-stimulated gene/protein-6; TECs, tubular epithelial cells; IL-1β, interleukin-1beta; TNF-α, tumor necrosis factor-alpha; MSCs, mesenchymal stem/stromal cells; TLR, Toll-like receptor; NF-κB, nuclear factor kappa-B; IL-10, interleukin-10; IαI, inter-alpha-inhibitor; HA, hyaluronan; ECM, extracellular matrix; TGF-β1, transforming growth factor-beta1; EMT, epithelial-mesenchymal transition; α-SMA, alpha-smooth muscle actin; NK cell, natural killer cell; ROS, reactive oxygen species; HC, heavy chain.

TSG-6 has a diverse functional repertoire of biological activities (Figure 1). Firstly, it can activate the inter-alpha-inhibitor (IαI) family of proteins to exert anti-inflammatory function. IαI is a Kunitz-type serine protease inhibitor in the plasma, consisting of two heavy chains and one light chain called bikunin.^{17, 23} TSG-6 catalyzes the transfer of the heavy chains onto HA, which stabilizes the ECM by cross-linking HA, and it also binds bikunin to potentiate its antiplasmin activity.²⁴

In addition, TSG-6 modulates the interaction of HA with CD44, a major cell surface receptor of HA that participates in the migration of leukocytes to inflammatory sites. Both TSG-6 and CD44 have a Link module, which is the HA binding domain. Interestingly, their interaction might have either pro- or anti-inflammatory consequences. Lesley et al.²⁵ observed that preincubation of HA with full-length recombinant TSG-6 or its Link module domain enhanced the binding of HA to cell surface CD44, thereby facilitating the rolling of leukocytes and their recruitment into inflammatory sites. On the other hand, high concentrations of TSG-6 in the presence of low concentrations of HA, as well as binding of soluble TSG-6-HA complexes to the surface of leukocytes, can suppress their adhesive interaction with the endothelium, thereby exerting an anti-inflammatory effect.²⁵ Moreover, TSG-6 interacts with CD44 on resident macrophages, either directly or in a complex with HA, presumably to dissociate CD44 from toll-like receptor (TLR)-2 and thereby limit TLR2-driven nuclear factor kappa-B (NF-κB) signaling and concomitant release of inflammatory cytokines.^26–28 Therefore, evidence supports the overall anti-inflammatory properties of TSG-6.

Furthermore, TSG-6 is the first identified soluble mammalian chemokine-binding protein²⁹; specifically, it inhibits chemokine-stimulated trans-endothelial migration of neutrophils by direct interaction with the glycosaminoglycan binding site of CXC-motif chemokine ligand-8 (CXCL8). Additionally, TSG-6 indirectly mediates the production of anti-inflammatory factors or metabolites. For example, it upregulates the mRNA expression of cyclooxygenase (COX)-2 in RAW 264.7 murine macrophage cells, resulting in the production of prostaglandins (PGs), especially PGD₂, whose metabolites are negative regulators of inflammation, such as 15-deoxy-Δ^12,14-PGJ2.³⁰ While COX-2 responses are often implicated in proinflammatory processes³¹, this notion is challenged by the finding of COX-2-derived metabolites of ω−3 polyunsaturated fatty acid in activated macrophages equipped with anti-inflammatory and anti-oxidative properties.^{32, 33} Notably, different stimulators of COX-2 may elicit different PG profiles. For instance, HA induces secretion of pro-inflammatory PGE₂ and thromboxane A2, which are crucial factors in inflammatory renal lesions,³⁴ whereas up-regulation of COX-2 by TSG-6 is accompanied by a predominant synthesis of anti-inflammatory PGD₂.³⁰ This might also be related to COX-2 expression in different cell types or compartments, as COX-2 expression in adipose tissue macrophages has been recently shown to suppress fat inflammation and dysfunction.³⁵ Therefore, the observed up-regulation of COX-2 by TSG-6 might be consistent with an anti-inflammatory property that depends on selective cellular activity.

TSG-6 is not constitutively expressed but is upregulated in various cell types (e.g., fibroblasts, peripheral blood mononuclear cells, proximal tubular epithelial cells [TECs], and vascular smooth muscle cells) during inflammatory processes stimulated by inflammatory cytokines such as TNF-α and IL-1.³⁶ TSG-6 has first been detected in synovial fluid from patients with arthritis,³⁷ and is emerging as a diagnostic and prognostic marker in body fluids^38–41 as well as a therapeutic tool in several diseases.¹⁷ Recombinant TSG-6 improved liver function by suppressing signal-transducer and activator of transcription (STAT)-3 activation, inhibiting hepatic oxidative stress, and inducing hepatic M2 macrophage polarization in mice with alcoholic hepatitis.⁴² TSG-6 also plays an important role in regulating wound closure and inflammation during cutaneous wound repair. TSG-6-null mice showed delayed wound closure and granulation resolution but elevated neutrophil accumulation compared to wild-type mice.⁴³ In addition, TSG-6 suppressed scar formation by reducing inflammation and inhibiting collagen deposition during wound closure.⁴⁴

Besides exogenous recombinant TSG-6 infusion or endogenous cellular sources of this molecule, many beneficial effects of stem cells have been attributed to TSG-6¹⁷. Mesenchymal stem/stromal cells (MSCs) reduced radiation-induced colorectal fibrosis through up-regulation of hepatocyte growth factor (HGF) and TSG-6 to control ECM deposition, and silencing HGF and TSG-6 blunted this effect.⁴⁵ Intrathecal injection of MSCs elicited neuroprotection by secreting TSG-6, targeting the TLR2/myeloid differentiation primary response-88 (MyD88)/NF-κB pathway in spinal-cord dorsal horn microglia.⁴⁶ In addition, MSC-derived exosomes protected against inflammatory bowel disease by restoring mucosal barrier repair and intestinal immune homeostasis due to their TSG-6 cargo.⁴⁷ Taken together, anti-inflammation is a crucial activity of TSG-6.

TSG-6 in renal inflammation

Given the central role of inflammation in renal pathophysiology, the potential role of TSG-6 in both acute and chronic kidney injury is starting to draw attention (Table 1). For example, TSG-6 displays remarkable anti-inflammatory effects in AKI. In a paraquat poisoning rat model, TSG-6 improved kidney function, decreased AKI score, and suppressed inflammatory cytokine mRNA levels.⁴⁸ TSG-6 also mediates a significant part of the tissue-protective properties of MSCs in the kidney. Bone marrow MSCs (BMSCs) improve kidney function and blunt tissue injury in ischemia/reperfusion injury-induced AKI accompanied by reduced infiltration of neutrophils into kidney tissue, whereas TSG-6-silenced BMSCs reversed these benefits.⁴⁹ In vitro experiments implied that the beneficial effects of TSG-6 in promoting TEC proliferation might be achieved by modulating inflammation.⁴⁹ While the underlying molecular mechanism has not been resolved, TSG-6 polarizes macrophages towards M2, a phenotype that enhances the cell cycle and promotes the proliferation of adjacent cells.⁵⁰ Hence, reduced inflammation may provide a favorable environment for tubular cell proliferation and self-repair.

Table 1.

A summary of studies to date investigating the effect of TSG-6 in different models of kidney diseases.

Study	Year	Kidney Disease/Model	Main Goal	Main Findings
Janssen et al. 68	2001	IL-1β or D-glucose stimulates TECs	Examine TECs synthesis of proteins and relate it to alterations of plasmin-protease activity	Human TECs constitutively express IαI. IL-1β or D-glucose induces TSG-6, which is associated with an inhibition of plasmin activity.
Bommaya et al. 73	2011	TGF-β1 stimulates EMT on TECs	Characterize the role of HA in the initiation of TGF-β1-triggered EMT by defining the role of TSG-6	TGF-β1-triggered TECs decrease E-cadherin and increase α-SMA and TSG-6 expression, and initiate HA cable disassembly, whereas TSG-6 knockdown produces loose HA-pericellular coats and provides potential resistance to EMT.
Kato et al. 56	2014	Acute cellular rejection in rat kidney transplantation	The beneficial effects of ADSCs on alloreactivity, mediated by TSG-6	ADSCs reduce T-cell infiltration and acute rejection rate, prolong graft survival, and increase TSG-6, which suppresses alloreactive T-cells by downregulating CD44.
Wu et al. 69	2014	Protein-overloaded milieu stimulates TECs	The effect of BMSC-derived TSG-6 on modulating tubular inflammation and interstitial fibrosis under an albumin-overloaded condition	Albumin induced tubular CCL-2, CCL-5, and TNF-α overexpression, which was suppressed by HGF, and upregulated α-SMA, FN, and collagen-IV, which were attenuated by TSG-6.
Xu et al. 48	2014	Paraquat poisoning AKI	The effect of TSG-6 on AKI following paraquat poisoning in rats	TSG-6 improved kidney function and AKI score, and suppressed inflammatory cytokines mRNA levels.
Maruyama et al. 57	2015	mAb 1-22-3-induced glomerulonephritis (an immunological type of renal injury); Adriamycin-induced nephropathy (a non-immunological type of renal injury)	The ability of DFAT cells to serve as a cell source for treatment of progressive renal diseases, mediated by TSG-6	DFAT cells reduce proteinuria and improve glomerulosclerosis and fibrosis in mAb-induced glomerulonephritis through TSG-6, but do not blunt injury in adriamycin-induced nephropathy.
Yoshida et al. 51	2018	UUO-induced renal fibrosis	The effect of TSG-6 derived from serum-free medium cultured MSCs on renal fibrosis	Serum-free medium cultured MSCs effectively ameliorate renal fibrosis in UUO and promote M2 macrophage polarization with higher TSG-6 mRNA expression; TSG-6 siRNA blunted these effects.
Chen et al. 49	2019	IRI-induced AKI	The effect of TSG-6 derived from BMSCs on IRI-induced AKI in rats	BMSCs improve kidney function and attenuate tissue injury in IRI-induced AKI by TSG-6 modulating inflammation.
Zhao et al. 52	2021	A renovascular disease swine model	The function of TSG-6 derived from ADSCs in the ischemic kidney	ADSCs improve renal function and alleviate fibrosis through release of TSG-6 to decrease inflammatory cytokines and polarize macrophages from M1 to M2 phenotype.
Utsunomiya et al. 59	2022	ANCA glomerulonephritis	The immunosuppressive effects of TSG-6 from DFAT cells implantation	DFAT cells suppress glomerular crescent formation and urinary protein excretion by TSG-6.

TSG-6, tumor necrosis factor-alpha-stimulated gene/protein-6; IL-1β, interleukin-1beta; TECs, tubular epithelial cells; TGF-β1, transforming growth factor-beta-1; EMT, epithelial-mesenchymal transition; HA, hyaluronan; α-SMA, alpha-smooth muscle actin; ADSCs, adipose tissue-derived mesenchymal stem/stromal cells; BMSCs, bone marrow MSCs; CCL2, C-C motif chemokine-2; CCL5, C-C motif chemokine-5; TNF-α, tumor necrosis factor-alpha; HGF, hepatocyte growth factor; FN, fibronectin; AKI, acute kidney injury; mAb, monoclonal antibody; DFAT, dedifferentiated fat; UUO, unilateral ureteral obstruction; IRI, ischemia-reperfusion injury; ANCA, antineutrophil cytoplasmic antibody.

Moreover, serum-free culture conditions enhance the immunosuppressive function of MSCs by leveraging the anti-inflammatory properties of TSG-6. Serum-free cultured MSCs ameliorated renal fibrosis induced by unilateral ureteral obstruction in rats more effectively than those cultured in 10% fetal bovine serum and showed higher gene expression of TSG-6.⁵¹ Transwell coculture of MSCs and THP-1 monocyte-derived macrophages showed that serum-free MSCs induce M2 macrophage polarization. Furthermore, treatment with TSG-6 siRNA blunted the effect of serum-free MSCs on downregulating monocyte chemoattractant protein-1 and TNF-α expression in human kidney (HK)-2 cells, implying that their anti-inflammatory capacity is mediated by TSG-6.⁵¹

We have shown that in a swine model of chronic renovascular disease, autologous adipose tissue-derived MSCs (ADSCs) improved renal function and alleviated renal fibrosis through the release of TSG-6, which reduced inflammatory cytokines and polarized macrophages from a proinflammatory M1 to an immunosuppressive M2 phenotype.⁵² In addition, we found that TSG-6 decreased M1 macrophage migration and adhesion in vitro. Therefore, the renoprotective effect of TSG-6 may be achieved by regulating immune cell function and phenotype. Exploration of the downstream mechanisms involved in the TSG-6 pathway revealed that intrarenal delivery of ADSCs downregulated TLR4 and MyD88 expression in the stenotic pig kidney, with levels of both proteins correlating inversely with renal vein levels of TSG-6.⁵² These findings are consistent with studies showing that TLR4 deficiency protects against tubulointerstitial inflammation⁵³ and fibrosis⁵⁴, and with observations in a model of inflammatory lung injury,⁵⁵ where recombinant TSG-6 exerted its anti-inflammatory effect on macrophages by interfering with the TLR4-MyD88 interaction and thus inhibiting downstream activation of NF-κB, STAT1, and STAT3.

In kidney transplantation models, ADSCs-derived TSG-6 blunts acute rejection of kidney allografts, which is representative of an allogeneic immune response. In a model of Dark Agouti rat kidneys transplanted into Lewis rats, ADSCs were injected into the donor through the renal artery before nephrectomy.⁵⁶ As a result, recipients with kidneys from the ADSC-injected donors showed a reduced acute rejection rate and prolonged graft survival, increased TSG-6 levels, and a decreased number of infiltrating CD4/CD8 T-cells compared with controls. In addition, recombinant TSG-6 suppressed alloreactive T-cells by downregulating CD44 in vitro. Overall, the study demonstrated that ADSCs attenuate acute rejection by secreting TSG-6 as well as through direct cell interaction.

Dedifferentiated fat (DFAT) cells show similar characteristics to MSCs and confer therapeutic effects in immunological renal injury.⁵⁷ DFAT cells implanted into a monoclonal antibody-induced glomerulonephritis rat model reduced proteinuria and improved glomerulosclerosis and interstitial fibrosis. Pertinently, renal cortical TSG-6 mRNA expression increased whereas IL-6, IL-12β, collagen-IV, and fibronectin mRNA levels decreased after DFAT delivery. Contrarily, TSG-6 siRNA-treated DFAT cells displayed blunted immunosuppressive and anti-fibrotic properties, again linking TSG-6 to their beneficial properties.⁵⁷ Interestingly, DFAT cells did not diminish glomerular and tubulointerstitial injury scores and rather increased proteinuria in rats with adriamycin-induced nephropathy. Given that adriamycin can induce early structural and functional injury in immunodeficient mice without infiltration by T- and B- lymphocytes,⁵⁸ it might induce glomerular and tubulointerstitial injury by direct toxic damage independent of immunological mechanisms. These observations indirectly imply that DFAT cells, and by extension TSG-6, improve renal degeneration in monoclonal antibody-induced glomerulonephritis predominately secondary to immunosuppressive mechanisms. Furthermore, in antineutrophil cytoplasmic antibody glomerulonephritis,⁵⁹ DFAT cells suppressed glomerular crescent formation, decreased urinary protein excretion, and markedly upregulated kidney expression of TSG-6 mRNA and protein level, whereas CD44 mRNA declined. Therefore, DFAT cells may modulate immunoactivity by suppressing the activity and infiltration of immune cells via TSG-6. Overall, these observations are consistent with an immunosuppressive function of TSG-6.

TSG-6 in renal fibrosis

The chronic persistence of renal inflammation may result in progression to renal fibrosis. Irrespective of etiology, TGF-β1 is a major driver of fibrotic response⁶⁰ and is capable of initiating and completing the entire epithelial-mesenchymal transition (EMT) course.⁶¹ This phenotypic conversion program is characterized by the loss of epithelial markers (like E-cadherin) and gain of mesenchymal features (including vimentin, alpha-smooth muscle actin [α-SMA], collagen-I, and fibronectin).⁶² TGF-β1 is elevated in the inflammatory environment, decreasing protease synthesis and increasing the level of protease inhibitors that block matrix degradation,^{63, 64} with the putative goal of closing wounds, repairing vulnerable tissue, or limiting the spread of inflammation, but resulting in more TGF-β1 production through a positive feedback loop.⁶⁵ Previous studies have demonstrated that plasmin activates matrix-bound latent TGF-β1.⁶⁶ As mentioned earlier, TSG-6 combined with bikunin, the IαI light chain, potentiates the unique feature of inhibition of plasmin activity,^{23, 67} which may, in turn, influence the activation of TGF-β1. In an in vitro study,⁶⁸ TSG-6 expression increased in proximal TECs stimulated by either IL-1β or D-glucose. Stimulation of TSG-6 was associated with an inhibition of plasmin activity, whereas immunoprecipitation of TSG-6 in these cell samples restored plasmin activity, confirming its dependence on stimulation of TSG-6. Therefore, one of the underlying anti-fibrotic mechanisms of TSG-6 involves inactivating TGF-β1 by suppressing plasmin activity.

MSC-derived TSG-6 may also show promise as a therapeutic tool against kidney fibrosis. BMSCs modulated renal tubular inflammation and EMT in a protein-overloaded milieu by overexpressing HGF and TSG-6. Further studies found that recombinant HGF treatment suppressed C-C motif ligand (CCL)-2, CCL-5, and TNF-α, and recombinant TSG-6 attenuated α-SMA, fibronectin, and collagen-I expression, and upregulated E-cadherin expression in TECs. Similar to colorectal fibrosis,⁴⁵ neutralizing HGF and TSG-6 eliminated the anti-inflammatory and anti-EMT effects of BMSCs in co-cultured proximal TECs subjected to albumin overload, suggesting that the anti-inflammatory and anti-fibrotic roles of BMSCs on TECs were mediated by HGF and TSG-6 via paracrine action.⁶⁹

Paradoxically, TSG-6 may also exhibit pro-fibrotic characteristics. HA surrounds proximal TECs in an organized pericellular matrix or ‘coat’, which is associated with cell migration; it also forms HA cables, which modulate TECs-mononuclear leukocytes interactions and appear to function as cell scaffolds.^{70, 71} Although HA is an important constituent of ECM,⁷² maintaining it at modest levels and with ordered structure is the cornerstone of a healthy renal cortex. Bommaya et al. demonstrated that TSG-6 expression increased when TGF-β1 initiated EMT in HK2 cells, while expression of E-cadherin decreased and that of α-SMA, CD44, and hyaluronan synthase-2 increased, with the disassembly of HA cables and replacement by dense HA pericellular coats.⁷³ Upon stable TSG-6 knockdown via short-hairpin-RNA, E-cadherin expression rose as did the production of loose HA-pericellular coats, whereas TGF-β1 treatment did not induce α-SMA or alter E-cadherin and pericellular-HA. Possibly, TSG-6 may actively modulate EMT by causing condensation and stiffening of HA pericellular coats.⁷³ This remains an interesting area for future research.

Prospects and challenges

The role of TSG-6 in inhibiting inflammation could constitute a promising therapeutic strategy for AKI and its transition into CKD. In addition, TSG-6 levels may serve as potential biomarkers for the diagnosis and prognosis of related kidney diseases. However, several issues remain to be clarified. First, it is essential to optimize the dose, timing, and delivery route of exogenous TSG-6 therapy to ensure efficacy. This is particularly relevant given the short half-life of the recombinant TSG-6 protein,⁷⁴ which may require encapsulation within cells or particles. Second, the kidney is a complex organ, with at least 41 cell populations of renal lineage identified.⁷⁵ The main type of cell expressing and secreting TSG-6 and which should constitute the specific target of TSG-6 remain to be identified. The potential of TSG-6 to both attenuate and mediate EMT should also be considered. Finally, despite promising experimental evidence, clinical trials are needed to verify the role and effectiveness of TSG-6 in inflammatory renal diseases.

Conclusion

TSG-6, identified about three decades ago, might emerge as a remedy for renal inflammation. With basic experimental studies recognizing its importance in inflammatory renal diseases comes the potential to target TSG-6 by designing appropriate clinical trials. Further studies are needed to develop strategies to target it to the kidney and specific cell types. Hopefully, future studies can harness the potential of TSG-6 and optimize its application.

Non-standard Abbreviations and Acronyms

TSG-6

tumor necrosis factor-alpha-stimulated gene/protein-6

IαI

inter-alpha-inhibitor

HA

hyaluronan

CXCL8

CXC motif chemokine ligand-8

COX-2

cyclooxygenase-2

AKI

acute kidney injury

IL-1β

interleukin-1beta

TNF-α

tumor necrosis factor-alpha

CKD

chronic kidney disease

IL-1Ra

interleukin-1 receptor antagonist

TGF-β1

transforming Growth Factor-beta1

GDF-15

growth differentiation factor-15

ECM

extracellular matrix

TLR

toll-like receptor

NF-κB

nuclear factor kappa-B

PGs

prostaglandins

TECs

tubular epithelial cells

STAT

signal transducer and activator of transcription

MSCs

mesenchymal stem/stromal cells

HGF

hepatocyte growth factor

MyD88

myeloid differentiation primary response-88

BMSCs

bone marrow MSCs

HK-2

human kidney-2 cell line

ADSCs

adipose tissue-derived MSCs

DFAT

dedifferentiated fat

EMT

epithelial-mesenchymal transition

α-SMA

alpha-smooth muscle actin

CCL-2

C-C motif ligand-2