Renal ischemia-reperfusion injury (IRI) is a common kidney disease that occurs as a result of kidney surgery, cardiac surgery, kidney transplantation, and disruption of the renal blood supply (1). During renal ischemia, renal tissues are affected by insufficient oxygen supply and accumulation of metabolites, leading to cellular damage and death. Then, the reperfusion process re-inflows blood into the kidney, but causes a series of inflammatory reactions and cellular damage that further aggravates kidney injury (2). The mechanisms of renal IRI include calcium overload, inflammatory response, reactive oxygen species damage and apoptosis, in which immune cell-mediated immune response also plays an important role (3–5). B lymphocytes are an important class of immune cells that usually produce antibodies, present antigens, and participate in immune regulation (6). More and more studies have shown that B lymphocytes play an important role in IRI. B lymphocytes are part of the inflammatory cells recruited to the kidney in renal IRI, involved in immune response exacerbates kidney damage. B cells participate in the immune response and inflammation by presenting antigens and secreting cytokines to cause further renal damage. And some B-cell subsets are immunosuppressive and play a protective role in IRI (7). In this review, we summarize the possible mechanisms of the role of B cells in renal IRI, including innate immune response, adaptive immune response, and negative immune regulation. This may help to provide new directions for the prevention and treatment of renal IRI in the future.

Renal IRI is one of the main causes of acute kidney injury (AKI), which can lead to acute damage to renal tissue. Studies have shown a bidirectional interaction between AKI and the immune system. AKI provokes intrarenal, systemic inflammation and both innate and adaptive immune system that play important roles in the pathogenesis of kidney injury. B cells are related to AKI as part of innate and adaptive immunity (8). IRI involves both ischemic and reperfusion processes, ischemia leads to intracellular hypoxia, which promote the production of reactive oxygen species (ROS) and lead to tissue damage (9). In addition, cellular depletion of ATP allows sodium and water to enter the cell, causing significant cellular edema (10). These processes can cause disruption of the cytoskeleton, cell membrane and mitochondrial membrane (11).

During reperfusion, the accumulation of ROS aggravates cellular damage and the increasing intracellular calcium ion levels activate calpain (12). It also leads to mitochondrial dysfunction, causing the release of cytochrome C, mitochondrial DNA (mtDNA) and other substances (13). These can cause the release of multiple inflammatory cytokines that recruit immune cells to the injured tissue. Endothelial cells also produce vasoactive substances such as Platelet derived growth factor (PDGF), leading to vasoconstriction (14). Ultimately, tubular cells and vascular endothelium undergo damage due to this complex pro-inflammatory cascade response. In addition, elevated endothelin and thromboxane, together with decreased prostacyclin, can also lead to vasoconstriction and further aggravate tissue damage (15). IRI is accompanied by aseptic inflammation in which both the innate and adaptive immune systems are involved. Activation of the immune system will occur through damage-associated molecular pattern (DAMP) binding to toll-like receptor (TLR) and activation of the complement system, leading to further damage to renal tissue, increased tissue immunogenicity as well as initiation of fibrosis and thus conversion to chronic kidney diseae (CKD) (16).

Renal IRI is inevitable during renal transplantation and remains a key factor affecting the survival of the transplanted kidney, which may lead to DGF and primary renal graft nonfunction (PNF) (17). Meanwhile, a large amount of clinical evidence shows that the severity of IRI is positively correlated with complications such as rejection and the incidence of transplanted kidney failure (18, 19).

Immune cells are involved in the immune response of the body and protect the health of the body by exerting immune effects under physiological conditions (20), but can exacerbate tissue injury under certain pathological conditions (21). In renal IRI, The immune response is activated to mediate kidney and distant organ damage (22). In this process, various groups of immune cells interact with each other to form an interaction network. Among them, B cells not only directly mediate immune injury and chemotaxis of other immune cells enriched in inflammation, but also act as antigen-presenting cells to activate adaptive immunity (23, 24). B cells and other immune cells can also migrate to distant organs through circulating blood flow and other pathways, and through the secretion of cytokines and other active substances to affect distant organs, further leading to damage to distant organs, thereby increasing the burden on the body (25).

Potential mechanisms of immune cell activation and recruitment in the kidney after IRI involve DAMP ( Figure 1 ). DAMP is an endogenous molecule expressed in cells under physiological conditions and released to the outside of the cell after tissue injury, which can effectively activate the immune system to initiate and maintain inflammatory responses by binding to pattern recognition receptors (PRR). DAMP molecules include high mobility group box 1 (HMGB1), histones, cell free DNA, IL-33, extracellular cold-inducible RNA-binding protein (eCIRP), and heat shock protein (HSP) (26). These histones released from necrotic tubules or DAMP such as HMGB1 activate TLRs on dendritic cells or macrophages and inflammatory vesicles in the cytoplasm to trigger the secretion of proinflammatory cytokines and chemokines in the ischemic kidney. TLR2 and TLR4 are similarly expressed on normal tubular epithelial cells and their expression is further increased after IRI (27). As part of intrinsic immunity, TLR4 plays an important role (28). Bergler et al. found that TLR4 was highly upregulated after renal IRI in a rat allogeneic kidney transplantation model and that high TLR4 expression was strongly associated with graft dysfunction (29). In addition, TLR4-deficient mice are protected from renal IRI and kidneys from donors with loss of TLR4 alleles exhibit fewer pro-inflammatory cytokines in the post-transplant kidney. Meanwhile, the onset of activation of intrarenal HIFs after IRI is upregulated mainly in renal tubular, mesenchymal and endothelial cells. Activation of intrarenal transcription factors such as nuclear factor κB (NF-κB), heat shock factor protein 1, and HIF-1α similarly stimulates the synthesis of a range of proinflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor (TNF) (30). Cytokines and chemokines are important mediators that regulate the recruitment of immune cells to the post-ischemic kidney, and they direct neutrophils and macrophages to the site of injury (31).

Neutrophils are the first immune cells to be recruited to the site of injury. Neutrophils may be involved in inducing renal injury by blocking renal microvessels and secreting oxygen free radicals and proteases. Neutrophils can produce oxygen radicals, release degranulating substances, platelet activating factors and other substances that damage kidney tissue, and can also release cytokines to recruit more neutrophils to form positive feedback, further aggravating tissue damage (32). Although resident macrophages are rare in normal kidneys, their numbers increase significantly in postischemic kidneys. IRI promotes endothelial damage and modification of heparin sulfate proteoglycans in microvascular basement membranes, facilitates their binding to L-selectin, and induces monocyte chemotactic protein 1 (MCP-1). These changes induce an early influx of monocytes and macrophages into the ischemic kidney. Monocytes adhere to blood vessels, and after IRI occurs, monocytes enter the tissue to form macrophages in response to the chemotaxis of damaged cells, inflammatory factors, and their neutrophils. Soon after kidney injury, macrophages become numerically dominant infiltrating cells (33). Macrophages can be divided into M1 and M2 according to their mode of action (34). M1, also known as classically activated macrophages, are activated to exert potent phagocytic activity and release several important cytokines, such as IL-1, IL-6, IL-8, IL-12, and TNF, as well as recruit neutrophils and induce apoptosis to promote the inflammatory cascade, thereby contributing to kidney injury (35). Therefore, inhibition of macrophage infiltration attenuated renal injury in a mouse renal IRI model (36). M2 product IL-10 and TGF-β, which are anti-inflammatory and moderate the immune response to tissue damage.

Many studies have revealed the important role of different lymphocyte subsets in IRI. The basic function of dendritic cells is to present antigens to T cells and act as messengers between the innate and adaptive immune systems. The binding of dendritic cells to the endothelium and their migration seems to be facilitated in the initial inflammatory response after IRI, leading to an increased ratio of myeloid to plasmacytoid dendritic cells, which can lead to delayed graft function and acute rejection. It has been found that T cells, especially CD4+ T cells, directly or indirectly promote the establishment of early kidney injury in IRI. T cell-targeting drugs, such as tacrolimus and mycophenolate mofetil, significantly attenuated early kidney injury after IRI. CD4, CD8 double-knockout mice were largely protected from early kidney injury, and the adhesion of their T cells to the tubular epithelial cells in vitro after hypoxia and reoxygenation was increased two-fold. Periplasmic transfer of T cells into these mice restored renal injury after IRI, suggesting that T cell deficiency enhances the protective effect of IRI on the kidney. The role of T cells appears to extend to the late stages of injury or repair of IRI and is not limited to the early stages of injury. Treg play a role in renal regeneration or nephroprotection.Treg promote tubular proliferation, which accelerates the repair process in the late and early recovery stages of injury after IRI (37, 38).

IRI, as a aseptic inflammatory process, is involved in the activation of both innate and adaptive immunity. In previous studies, activated B cells were observed to be enriched in the kidney after IRI. These activated B cells can be divided into B1 cells and B2 cells according to the intrinsic or adaptive immune function they perform (39). Among them, B1 cells are intrinsic immune cells, accounting for about 5% to 10% of the total B cells, and play an important role in the early stages of the immune response. B1 cells can be further subdivided into subpopulations B1a and B1b based on the expression of the surface marker CD5. B1 cells comprise the majority of neonatal B cells and are derived primarily from fetal liver and omentum. In adults, B1 cells are found mainly in the pleural and peritoneal cavities and respond to T cell-dependent antigens by secreting polyreactive IgM antibodies (40). B2 cells, on the other hand, are the main cells that secrete antibodies to participate in the humoral immune response, appear relatively late in individual development, are localized in the follicular area of peripheral lymphoid organs (41). After maturation in the bone marrow, B cells migrate to lymphoid organs. B cells are activated in the spleen or other secondary lymphoid organs by contact with antigen via BCR. There are very few B cells in the normal kidney. In renal IRI, due to chemokine effects, activated B lymphocytes accumulate in the renal tissue (42). These activated B lymphocytes may be involved in the inflammatory response and immune response through the release of cytokines and chemokines (43). Also, B lymphocytes play a role in the pathological process by producing antibodies to mediate immune injury (44). These antibodies may activate adaptive immunity and trigger an inflammatory response by binding antigens on kidney tissue. At the same time, this process can exacerbate IRI and post-IRI rejection and chronic fibrosis ( Figure 2 ).

Given the important role played by B-cell kidney IRI process, targeting B cells and antibodies or increasing Breg may be effective in reducing IRI. Current clinical therapeutic approaches that target B cells include killing B cells directly, modulating B cell function, and inhibiting molecules that are dependent on B cell survival (78). According to the different mechanisms of action, drugs acting on B cells are classified as anti-CD20(CD20 expressed in B cells at all developmental stages except plasma cells and can affect the proliferation and differentiation of B cells by regulating the transmembrane flow of calciumions (79).) class drugs, anti-CD19 (CD19 is a key signaling molecule in the process of antigen recognition by B-cell surface receptors) class drugs, anti-B cell activating factor [BAFF, a crucial factor for B cell survival, binds to the B cell surface receptor to support B cell survival, proliferation and differentiation (80)] and Bruton’s tyrosine kinase [BTK, a key kinase in the BCR signaling pathway that is involved in B-cell proliferation, differentiation and apoptosis (81, 82)] inhibitors (83). However, these drugs and methods of killing B cells or inhibiting B cell function carry a significant risk of immunocompromise as well as pathogen infection, and their use in the prevention and treatment of renal IRI is generally considered to be more costly than it is worth. Moreover, nonspecific removal of B cells suppresses the immunoregulatory function of Breg cells, which is very detrimental to overall immune homeostasis.

Plasma replacement is the non-selective removal of macromolecules, such as antibodies, complement, immune complexes and coagulation factors, from plasma by physical means. The use of melphalan and plasma exchange to prevent antibody-mediated rejection in renal transplantation has been advanced only in pre-sensitized patients, and we do not know their role in the prevention of renal IRI (84). Given the negative effects of B1 cells in the early stages of renal IRI, blocking B1 cell function is a potential direction worth considering. The mouse data suggest that CCL7 blockade may be a useful therapeutic strategy to reduce the infiltration of inflammatory cells into the kidneys, thereby improving AKI, without affecting the systemic mobilization of bone marrow cells, which may contribute to the defense against infection (47). Because B cells are an important source of CCL7, observations in siglecg ^-/- mice suggest that targeting this cell subpopulation, particularly B1a cells, may be particularly useful. In this regard, siglecg itself may be a direct target: siglecg is a surface glycoprotein with an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic structural domain that allows it to inhibit bcr-mediated activation (85). Therefore, the use of agonists (e.g., sialic acid) bound to siglecg may have therapeutic potential. One problem with inhibiting B1a function is that this subpopulation may also be an important source of the immunomodulatory cytokine IL-10 (86). Thus, inhibition of this subpopulation may be undesirable given the potential beneficial role of regulatory B cells in AKI models. In addition, the relatively small number of B1 cells in humans and the absence of specific markers also make translation to the clinic relatively difficult. CXCL13 serves as a major cytokine for B-cell chemotaxis, and the current study also established that CXCR5-positive B cells are enriched at sites of inflammation by CXCL13 released by injured renal tubular cells (87). Blocking CXCL13-CXCR5 may be effective in inhibiting B cell enrichment in the damaged kidney. In addition, CXCL13 release may also be regulated through TLR2 and IL-10 dependent mechanisms (88). Complement activation may also affect immune cell-mediated secretion of CXCL13 release. Thus, inhibition of CXCL13 may exert its protective effects against renal IRI through pathways other than B cells. It is important to note that CXCR5 expression was not limited to B cells; macrophages and Tfh cells were also identified as CXCR5-positive. Blocking CXCL13-CXCR5 may cause a decrease in the chemotaxis of these cells (52). Inhibition of specific T-cell activation and complement function has a positive role in renal IRI, but these studies lacked evidence of a B-cell pathway of action. Therefore, the primary place of direct blockade of T-B cell action and complement-B cell activation in protecting against renal IRI remains uncertain. By increasing the number of Breg and thus inhibiting the function of other immune cells and reducing the inflammatory response, exogenous infusion of Bregs may therefore be a new therapeutic route for the treatment of IRI. However, exogenous induction of B-cell differentiation to Breg is also a potential therapeutic modality and is simpler since in vitro isolation and culture of Breg takes longer time and carries more risk of contamination (89, 90). Fang et al. successfully induced Breg production using anti-CD45RB and produced the same therapeutic effect as exogenous direct infusion of Breg, both of which reduced renal IRI (76).

There are still no immune drugs specific for renal IRI, and there are only a few clinical trials targeting immune cells (91–93).

In this review, we describe the mechanisms of renal IRI, the role played by immune cells, especially B cells, in IRI through multiple pathways, and explore potential therapeutic directions to mitigate IRI by targeting B cells and exogenous infusion of Breg. For renal IRI, we found that there is no single therapeutic approach that can fully address the renal effects of IRI, and therefore a combination of therapeutic approaches may be required. In this paper, we briefly describe some new therapeutic targets in terms of B cells, such as cytokine, T cell, plasma replacement and promotion of B cell differentiation to Breg. Although sufficient basic experimental and clinical data are needed before clinical practice, reducing renal IRI by acting on B cells is a promising research and therapeutic direction.

HF, JL, JS and GF conceived the conception, analyzed data, and wrote the manuscript. JFL conceived the conception and performed critical revision of the manuscript. All authors read and approved the final manuscript. HF and JL contributed equally to this work.