Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a mild rash, joint pain and multi-organ damage. The global SLE incidence and prevalence are estimated to be 5.14 (1.4 to 15.13) per 100,000 person-years and 43.7 (15.87 to 108.92) per 100,000 individuals (1). The hallmark of SLE is the defective clearance of dead cells by the immune system and the loss of tolerance to endogenous antigens such as double-stranded (ds)DNA, resulting in the abnormal activation of the immune system. This activation leads to immune-mediated attacks on organs and tissues, including lung, gut and kidney involvement (2). In particular, the kidneys are affected, leading to the development of lupus nephritis (LN) as the most severe manifestation of SLE and the common cause of morbidity and mortality in patients with SLE. In patients with SLE, >60% suffer from LN, and 40% of them progress to end-stage renal disease (ESRD) (3,4), which endangers the lives and health of the individuals, with the exact incidence contingent upon ethnicity and sex (5). The immune system contributes to the development of SLE. The two main cell types in the adaptive immune system, B cells and T cells, are both indispensable for the development of LN. B cells are pathogenic in SLE through the autoantibodies (such as anti-dsDNA antibodies and anti-nucleosome antibodies) and cytokines they produce. T cells drive both the systemic and intra-renal activation of B cells (6). In addition, genes for SLE also cause LN. Renal aggression during SLE is triggered by genes that undermine immune tolerance and stimulate autoantibody production. These genes may collaborate with other genetic factors to amplify innate immune signaling and type α interferon (IFN-α) production, consequently leading to the recruitment of leucocytes, inflammatory mediators and autoantibodies into end organs, notably the kidneys (7). Currently, high-doses of hormones (glucocorticosteroid) combined with immunosuppressants (methotrexate) are first line therapeutics for LN treatment. Short-term complete renal response rates are only 10–40% at 12 months, long-term outcomes have not improved further, and as many as 30% of LN patients will still progress to ESRD (8,9).

Podocyte injury is involved in the occurrence and development of LN, a disease that is associated with the progressive loss of renal function and various renal pathological features, including mesangial cell proliferation and subendothelial immune complexes. Podocytes are terminal epithelial cells that protrude into the glomerular urinary space and constitute an important component of the glomerular filtration barrier. Immune complex deposition in the renal tissues activates the complement system and thereby contributes to the failure in the efficient clearance of cellular fragments, triggering both the innate and adaptive immune systems. The production of cytokines such as IFN-α stimulates the antigen presentation and overactivation of T and B cells (7). Ultimately, additional inflammatory cytokines and chemokines promote the recruitment of inflammatory cells to the kidney and cause podocyte injury in the glomerulus (10). Numerous studies have reported the involvement of podocyte injury in LN (11–13) and have suggested that podocytes can serve as biomarkers of LN activity (14). A new concept called ‘lupus podocytopathy’ has been proposed (15), which refers to patients with LN with normal glomeruli but a diffuse disappearance of foot processes and podocyte damage. However, podocyte injury in patients with LN with normal glomeruli is often overlooked in clinical practice, which delays timely treatment and accelerates the deterioration of renal function. Therefore, investigating the role of podocyte injury in LN is warranted.

The immune microenvironment is considered as the environment of the local immune response. It is composed of diverse populations including infiltrating immune cells, immune molecules and humoral components. Immune complex deposition, local complement activation, along with immune cell recruitment and local intrarenal cytokine signaling account for glomerular injury in the LN immune microenvironment (10). Renal immune cells accumulate in the kidneys of the patients with LN, which involves the formation of tertiary lymphoid structures (TLS) (16). The TLS consists of immune cells, cytokines and resident renal cells in LN, and the activation of immune cells triggers a transient aggravation of resident cell injury and even the production of autoantibodies within the kidneys, exacerbating disease progression (17).

LN develops from a loss of immune balance to ubiquitous autoantigens, which is a result of inflammation and immune responses. Although the immunomolecules and immune cells in the renal immune microenvironment have important roles, the underlying mechanisms of the immune responses in the podocyte injury of LN remain unclear. The present review aimed to summarize the current understanding of the immune microenvironment of podocytes in LN, provide an update on their interaction mechanisms and offer the rationale for the podocytes as novel therapeutic targets in the treatment of LN.

LN is the most common complication of SLE, and proteinuria and hematuria are the primary clinical manifestations. The salient features of LN are associated with the deposition of immune complexes, which cause an inflammatory and immune response in the kidney (18). In vivo apoptosis or secondary necrosis (19) is responsible for the chromatin fragment exposure. The exposed DNA or nucleosomes bind with corresponding autoantibodies to form immune complexes and deposit onto the glomerular basement membrane. Concurrently, after associating with immune complexes in the glomeruli, nucleosomes within necrotic intrinsic glomeruli cells form in situ immune complexes containing both DNA and nucleosomes (20).

The nucleic acid components of the immune complexes collectively stimulate intrarenal inflammation by binding to toll-like receptors (TLRs) and Fc receptors (FcRs) or by activating immune responses through the complement cascade. Additionally, the ligation of TLRs induces the maturation of plasmacytoid dendritic cells (pDCs) and facilitates the secretion of proinflammatory cytokines and chemokines including interferon (IFN)-α (21,22). Secreted IFN-α promotes the activation of antigen-presenting dendritic cells (DCs), thereby promoting the differentiation of self-reactive B cells to plasma cells and enhancing the production of memory T cells, which form germinal center structures (23).

B-cell activating factor (BAFF) emerges as an inducer of B cell proliferation, differentiation and maturation through the CD40 ligand (CD40L) and CD28, on the surface of T cells migrating into the glomeruli, binding with CD40 and B7 on B cells, respectively (17). Subsequently, the autoantibodies produced bind to autoantigens and deposit in situ in the kidney. In addition to secreting antibodies, activated B cells, as a type of antigen-presenting cell (24), promotes the activation of pathogenic T cells to secrete proinflammatory cytokines such as IL-6 and TNF-α, and facilitate the recruitment of macrophages and DCs into the glomerulus and the tubulointerstitium (25). Immune cells also undergo intrarenal proliferation and activation by binding to the FcRs of immune complexes. Activated neutrophils and macrophages secrete reactive oxygen species and proteases, which directly damage the kidneys (26). In addition, immune complexes also activate the complement pathway to form membrane attack complexes, releasing anaphylatoxins to promote inflammatory reactions and accelerate the progression of LN (27) (Fig. 1).

The podocyte, a terminally and highly differentiated epithelial cell located in the urinary space, consists of a foot process and an apical surface domain. Given that podocytes act as essential components of the glomerular filtration barrier, the apical surface domain carries a negative charge and restricts the passage of negatively charged proteins (28). Foot processes attach to the glomerular basement membrane through integrins, syndecans, dystroglycan and other adhesion molecules (28). During podocyte development, a number of large extensions are formed by the epithelial cells, therefore, primary foot processes split into secondary and tertiary processes, which are abundant in microtubule structures (29). The foot processes are primarily composed of actin, which constitutes the cellular cytoskeleton of the podocyte. The function of actin is to connect the apical and basal membrane domains, as well as the slit diaphragm. The parallel contractile actin bundles are controlled to regulate the permeability of the filtration barrier (30). Destruction of podocyte actin leads to podocyte injury, disappearance of foot process fusion, damage to the filtration barrier and to proteinuria. Adjacent foot processes interdigitate with each other, forming slit diaphragms that anchor to the glomerular basement membrane. Nephrin, podocin, CD2-associated protein (CD2AP) and other molecules compose the slit diaphragm, participating in intracellular signaling and the formation and maintenance of the filtration barrier (Fig. 2).

Nephrin, a member of the immunoglobulin superfamily, interacts with the actin cytoskeleton through Nck adapter proteins and maintains the integrity of the podocyte structure and the filtration barrier (29). Nephrin affects the assembly of actin polymers in cell membranes. Decreased levels of nephrin leads to abnormal tertiary podocytes, loss of normal polarity and abnormal intercellular junctions, as a result of proteinuria. Neph1 is another transmembrane protein located near to nephrin in the cell membrane (31). Neph1, a major regulator of actin dynamics, is indispensable in maintaining normal slit diaphragm function. The phosphorylated nephrin-Neph1 complexes can lead to the reassembly of actin complexes, exerting irreversible effects on podocyte filtration function (32). Podocin is a membrane-associated protein that is crucial for signal transduction of the nephrin-Neph1 complex. The reduction in nephrin level caused by podocin mutations will alter the signaling of the nephrin-Nephl complex and result in an impaired podocyte slit diaphragm (33). Podocin also regulates cellular cytoskeletal dynamics through the activity of transient receptor potential cation channel subfamily C member 6 (TRPC6). TRPC6 is a non-selective, calcium-permeable cation channel in the plasma membrane of podocytes, which stabilizes the actin cytoskeleton of podocytes to sense changes in pressure, fluid flow or filtration rate (34). CD2AP is a cytoplasmic protein that interacts with nephrin and podocin and also takes part in the actin filament assembly in the slit diaphragm of podocytes through cellular signal transduction (35). The downregulation of these slit diaphragm proteins can lead to the structural and functional damage of podocytes and the production of proteinuria.

The occurrence and progression of LN involves multiple pathways, including abnormal cell death, autoantibody production, immune complex deposition, complement activation and the increased activation of immune cells (for example, T and B cells). Immune complex deposition predominates in the development of LN, and the majority of LN classifications by the International Society of Nephrology and the Renal Pathology Society involve immune complex deposition (Table I). Additionally, foot process fusion and podocyte injury have been observed in different classifications of LN (36). The deposition of immune complexes in the kidneys takes place by various mechanisms and activates complement components, inducing damage to podocytes through both the innate and adaptive immune responses. Furthermore, podocytes express immunomolecules and participate in immune responses (37) (Fig. 3).

Previously, four lupus mouse models have been established, including spontaneous lupus mouse models, induced lupus mouse models, genetically modified lupus mouse models and humanized lupus mouse models. Currently, the spontaneous lupus mouse model is commonly used to study the interaction between podocytes and the immune microenvironment. The spontaneous lupus mouse models include New Zealand Black (NZB), NZB × New Zealand White (NZB/W) first filial generation (F1), MRL/lpr and BXSB/Mp (BXSB/Yaa). These models produce SLE-like autoimmunity, with the production of autoantibodies including anti-nuclear, anti-dsDNA and anti-histone. Clinical manifestations of SLE have also been observed, such as immune complex-mediated glomerulonephritis and polyclonal hypergammaglobulinemia and foot process effacement (88) (Table II).

NZB/W F1 mice are a model for studying renal lesions in SLE. These mice have a susceptibility to autoimmunity and exhibit podocyte damage, reduced nephrin and podocin expression levels and proteinuria production. Immune complex deposition and crescent formation can be observed in the glomeruli, with mild mesangial hyperplasia in the early stages of murine development and focal and diffuse proliferative histological forms in the late stages of murine development, culminating in renal failure (89).

MRL/lpr mice are a model of spontaneous recessive mutant lymphocyte proliferation that can present with immune complex deposition-mediated glomerulonephritis, with a proliferative LN histological pattern characterized by endothelial and mesangial cell proliferation and thickening of the basement membrane (90). MRL/lpr mice are commonly used to investigate the mechanisms of podocyte injury and specific pathogenic mechanisms in diseases affecting the kidneys. CFH deficiency in this mouse model leads to immune complex deposition, loss of podocyte foot processes, accelerated renal injury and LN progression (45). When MRL/lpr mice are stimulated with LPS, levels of proinflammatory cytokines increase in the serum, and there is damage to the podocytes in the kidney, as well as increased urinary albumin (91).

BXSB/Yaa mice are a male lupus-like autoimmune disease model (92) that develops severe immune complex-mediated glomerulonephritis with podocyte injury and foot process effacement. This model also develops membranoproliferative LN with IgG and C3 deposition in the mesangium (46). The overexpression of the TLR was correlated with urinary albumin levels and mRNA levels of the nephrin in the BXSB-Yaa mice, which are commonly used to investigate the interaction between TLRs and podocytes. The BXSB/Yaa mouse model is the result of a gene mutation that causes translocation of the terminal region of the X chromosome to the Y chromosome, leading to TLR7 gene duplication, which increases TLR7 expression levels (93). Additionally, BXSB/Yaa mice demonstrate overexpression of the TLR8 in the glomerulus, which is negatively correlated with podocyte markers (nephrin, podocin and synaptopodin), inducing autoimmune responses. The mRNA expression level of TLR8 is positively correlated with urinary albumin, suggesting the involvement of TLR8 in the process of podocyte injury (50).

New animal models are expected to be established to explore the specific pathogenic mechanisms of renal intrinsic cell autoantibodies in kidney disease. This will shed light on novel pathways leading to renal damage in LN.

In the last decade, prominent advances have been made in studying the structure and function of podocytes. Anifrolumab is a human monoclonal antibody targeting the type I IFN receptor subunit 1 and is the first type I IFN receptor antagonist approved by the US Food and Drug Administration for the treatment of SLE in adult patients. Meanwhile, anifrolumab has been investigated as a promising strategy for the treatment of LN in clinical trials (94–96). A large randomized placebo-controlled trial suggested that neutralizing type I IFN receptors expressed by podocytes can effectively reduce proteinuria in patients with LN (97). Tacrolimus, a calcineurin inhibitor, can reduce proteinuria and improve kidney function in mice with lupus and patients with LN (98), while stabilizing the podocyte cytoskeleton and suppressing podocyte apoptosis, partially protecting podocytes from injury in LN (99). Baricitinib, a selective inhibitor of JAK1 and JAK2, is commonly used for rheumatoid arthritis treatment. Recent a study has revealed that baricitinib demonstrates benefits in inhibiting systemic autoimmunity in MRL/lpr mice and improves the lupus-like phenotype. It has been identified that baricitinib can inhibit the JAK/STAT pathway in podocytes, restore the abnormal podocyte structure caused by inflammation, and thus prevent renal damage (100). Greka et al (71) revealed that abatacept, a co-stimulatory blocker of B7-1, suppresses T cell activation and promotes integrin activation in podocytes. It also inhibits podocyte migration and prevents podocyte damage, which improves proteinuria in patients with LN.

Podocyte damage is reversible in LN, and actin is able to restore foot processes and reorganize the podocyte cytoskeleton. These studies illustrate a therapeutic target of podocytes in the glomerulus and immune cells in the immune microenvironment for precise treatment of LN, as they reduce systemic side effects of drugs, relieve proteinuria symptoms and improve disease progression.

Podocytes are glomerular epithelial cells, and the majority of all kidney diseases lead to podocyte injury. There is evidence that podocytes are important intrinsic cells of the kidney, which confer immune cell functions to promote the occurrence and development of LN. The manifestation and pathology of SLE in murine models, especially NZB/W F1 and MRL/lpr mice, are identical to that in patients with LN and have similar immune mechanisms. These help to further investigate the interaction mechanisms between podocytes and the renal immune microenvironment in LN. Recently, a number of studies have revealed that current therapies used to treat autoimmune diseases exhibit a direct protective effect on podocytes, alleviating the occurrence of proteinuria. These findings provide insights into targeted therapy for kidney diseases. Numerous studies have confirmed that LN podocytes participate in the innate and adaptive immune processes and interact directly with cells and molecules in the immune microenvironment. However, the mechanism of their interaction has not been thoroughly investigated. Therefore, further studies are needed to elucidate the interactions between LN podocytes and the local immune cells of the kidney, especially T and B cells. Targeting these pathogenic pathways might enable a more personalized approach to the treatment of LN and lead to improved outcomes for patients with LN.