Complementing Testicular Immune Regulation: The Relationship between Sertoli Cells, Complement, and the Immune Response
Abstract
:1. Introduction
2. Sertoli Cell Immune Regulation in the Testis
3. The Complement System
3.1. The Cascade of Complement Activation
3.1.1. Activation
3.1.2. Response Expansion
3.1.3. Termination
3.2. Functions of Complement
3.2.1. Three Main Outcomes of Complement Activation
Complement Receptor | Ligands | Cellular Distribution | Role in Complement | Role in Male Reproduction | References |
---|---|---|---|---|---|
Type 1 complement receptor (CD35, CR1) | C3b, C4b, iC3b | T cells, B cells, macrophages, neutrophils, dendritic cells, eosinophils, erythrocytes | Cofactor for cleavage of C3b and C4b, opsonization, clears immune complexes | Associated with testicular interdigitating dendritic cell tumors; any role in reproduction is unknown | [52,55,56,57] |
Type 2 complement receptor (CD21, CR2) | C3d, C3dg, iC3b | B cells, dendritic cells, epithelium | Coreceptor in B cell activation, sequesters antigens in lymphoid germinal centers | Unknown | [52,56] |
Type 3 complement receptor (CR3, CD11b/CD18) | iC3b, ICAM-1 | Macrophages, dendritic cells, neutrophils, natural killer cells | Opsonization, adhesion of leukocytes to endothelium | Unknown | [52,58,59] |
Type 4 complement receptor (CR4, CD11c/CD18) | iC3b | Macrophages, dendritic cells, neutrophils, natural killer cells | Opsonization, adhesion of leukocytes to endothelium | Unknown | [52,58,59] |
C1q binding protein (C1QBP, gC1q receptor, gC1qR) | C1q | T cells, B cells, monocytes, dendritic cells, neutrophils, endothelium | Opsonization, mitochondrial fitness, T cell activation and proliferation, regulates cellular cytotoxicity of B cells, chemotaxis induction | Unknown | [31,60,61] |
Complement receptor of immunoglobulin family (CRIg) | C3b, iC3b | T cells, macrophages | Stabilizes Tregs, enhances Treg response, opsonization | Unknown | [62,63,64,65] |
C3a receptor (C3aR) | C3a, C3a-DesArg | T cells, B cells, macrophages, dendritic cells, myeloid cells | Leukocyte chemotaxis and extravasation, T cell activation and proliferation, regulates cellular cytotoxicity | Unknown | [49,66] |
C5a receptor 1 (C5aR) | C5a, C5a-DesArg | T cells, B cells, macrophages, dendritic cells, myeloid cells | Leukocyte chemotaxis and extravasation, T cell activation and proliferation, regulates cellular cytotoxicity | Unknown | [49,66] |
C5a receptor 2 (C5L2) | C5a, C5a-DesArg | T cells, neutrophils, macrophages, dendritic cells | Negative regulator of C5aR, decoy receptor, proinflammatory and anti-inflammatory functions | Unknown | [67,68] |
3.2.2. Anaphylatoxin Functions
4. Complement Regulation
4.1. Activation Pathway Inhibitors
4.2. C3 and C5 Convertase Inhibitors
4.3. Terminal Pathway Inhibitors
4.4. Anaphylatoxin Inhibitors
5. Complement Anaphylatoxin Modulation of Immune Cells
5.1. Antigen Presenting Cells
5.2. T Cells
6. Sertoli Cell Regulation of Complement
7. Discussion
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Complement Inhibitor | Target | Distribution | Role in Complement | Role in Male Reproduction | References |
---|---|---|---|---|---|
Activation pathway inhibitors | |||||
C1INH (C1 inhibitor, SERPING1) | C1r, C1s | Serum protein (0.21–0.341 μg/mL) | Dissociates C1r and C1s from C1q, controls vascular permeability | Deficiency causes hereditary angioedema, which may lead to testicular swelling | [78,79,80,81,82] |
C1QBP (C1q inhibitor, C1INH, gC1qR,) | C1q | Serum protein (38 μg/mL) | Binds C1q to prevent further C1 complex assembly | Unknown | [83,84,85,86] |
C4BP * (C4 binding protein, proline rich protein, PRP) | C4b | Serum protein (300 μg/mL) | Degrades C4b with Factor I, prevents assembly of classical and lectin pathway C3 convertases | Does not affect fertility, but may be involved in male reproduction, but the role is unknown | [87,88] |
CD35 * (Type 1 complement receptor, CR1) | C1q, MBL, C3b, C4b, iC3b | Membrane protein | Associates with C1q or MBL to prevent activation, degrades C3b to iC3b and C3f, degrades iC3b to C3c and C3d,g, acts in antigen presentation, may generate Tregs | Associated with testicular interdigitating dendritic cell tumors; any role in reproduction is unknown | [57,88,89] |
COMP (Cartilage oligomeric matrix protein) | C1q, MBL, C3 | Serum protein (4–10 μg/mL) | Associates with C1q, MBL, and C3 to prevent further classical or lectin pathway activation | Unknown | [90,91,92] |
Factor H (Reconnectin) | Bb, C3b | Serum protein (135–250 μg/mL) | Degrades C3b with Factor I, accelerates dissociation of Bb from C3 convertase | Detected in seminal plasma, protects sperm from complement-mediated destruction in male and female reproductive tracts | [93,94,95] |
PTX3 (Pentraxin-related protein, TNF-inducible gene 14 protein) | C1q | Serum protein (0.002 μg/mL) | Binds C1q to prevent further C1 complex assembly | Detected in seminal plasma, associates with immotile spermatozoa, correlated with normal spermatozoa; important in female fertility | [96,97,98] |
SMAP-1/SMAP-2 (MBL/ficolin/CL-associated protein, MAP44, MAP144) | MASP-1/2 | Serum protein (1.4 μg/mL) | Prevents MASP-1/2/3 from binding MBL | Unknown | [99,100,101] |
SUSD4 (Sushi-domain containing protein 4) | C1q, MBL | Membrane protein | Associates with C1q or MBL to prevent cleavage of C2 | Unknown | [90,102,103] |
C3 and C5 convertase inhibitors | |||||
CD141 (thrombomodulin, granulocyte macrophage-colony stimulating factor, GM-CSF) | C3, C3a, C3b, C4b, C5a | Membrane and serum protein (0.003–0.3 μg/mL) | Causes decay of convertases; inhibits anaphylatoxins | Marker for adenocarcinoma of the rete testis; deficiency may contribute to recurrent miscarriage | [104,105,106,107] |
CD46 * (Membrane cofactor protein, MCP) | C3b, C4b | Membrane protein | Degrades C3b/C4b with Factor I, dissociates C3b/C4b from C3/C5 convertases, important for Th1 response, contracts Th1 cells to Tregs | Located on the acrosomal membrane; Important in stabilizing the acrosome reaction during egg-sperm fusion | [108,109,110,111,112,113,114] |
CD55 (Decay accelerating factor, DAF) | C3, C3b, C5, C5b | Membrane and serum protein (0.004–4 μg/mL) | Accelerates decay of C3 and C5 convertases, inhibits C3 and C5 cleavage, regulates T cell tolerance | Detected on the inner acrosomal membrane of sperm; May protect sperm from female complement-mediated destruction; May have other roles in reproduction | [115,116,117,118] |
CFHR1-5 * (Complement factor H related proteins) | C3b, C3d,g, iC3b | Serum protein (6–100 μg/mL) | Degrades C3b with Factor I, binds C3b, interacts with C3d,g and iC3b, binds heparin | Unknown | [119] |
CRIg (Complement receptor of immunoglobulin, V-set Ig domain-containing 4) | C3b, iC3b | Membrane protein | Associates with C3b to inhibit alternative pathway, binds iC3b, negatively regulates T cell activation | Unknown | [62,64,65,120] |
CSMD1 * (CUB/sushi domains protein 1) | C3b, C7 | Membrane bound | Degrades C3b with Factor I, inhibits binding of C7 to C5b-6 | Located at the interface of germ cells and somatic cells; Mutations in this protein are associated with increased C3 deposition in testis and infertility in males and females | [121,122,123] |
Factor I (ARMDI3, AHUS3) | C3b, C4b | Serum protein (35 μg/mL) | Degrades C3b and C4b, requires cofactor for activation | Unknown | [124] |
PLG (plasminogen) | C3, C5 | Membrane and serum protein (75 μg/mL) | Causes decay of convertases | PLG located on female germ cells reduces penetrant sperm; PLG activators are associated with testicular restructuring in development | [125,126,127,128,129] |
VWF (von Willebrand Factor) | C3b | Serum protein (50–200 μg/mL) | Cleaves C3b to iC3b | Unknown role in male reproduction; Defective VWF increase miscarriage rate | [130,131,132] |
Terminal pathway inhibitors | |||||
CD59 (Protectin) | C8 | Membrane protein | Interacts with C8 to prevent C9 recruitment, alternative ligand for CD2, activates T cells | Expressed on the inner acrosomal membrane; Protects sperm from female complement; Correlated with testicular androgen synthesis | [90,115,118,133,134] |
Clusterin (CLU, sulphated glycoprotein-2, apolipoprotein J) | C6, C7, C8, C9 | Membrane and serum protein (50 μg/mL) | Binds C6, C7, C8, and/or C9 to inhibit MAC assembly, forms soluble complexes with C5b-9, acts with vitronectin to prevent MAC insertion into membrane | Expressed at high levels in seminal plasma; May influence maturity processes of sperm; Prevent male stress proteins from aggregating; May contribute to sperm survival in the female reproductive tract | [135,136,137,138] |
Vitronectin (VTN, Serum spreading protein, S-protein, plasminogen activator inhibitor-1 binding protein, epibolin) | C7 | Plasma protein (200–400 μg/mL) | Interacts with C5b-7 to prevent C8 binding, acts with clusterin to prevent MAC insertion into membrane, forms soluble complexes with C5b-9, promotes cell adhesion and migration in tissue repair | Released within spermatozoon after acrosome reaction; Promotes sperm aggregation and sperm adherence to oocyte | [136,139,140,141] |
Anaphylatoxin inhibitors | |||||
CPB/CPN (Carboxypeptidases B, N) | C3a, C5a | Serum protein (30 μg/mL) | Degrades C3a/C5a to C3a/C5a desArg, inhibits migration of leukocytes, inhibits fibrinolysis | Unknown | [142,143,144,145] |
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Washburn, R.L.; Dufour, J.M. Complementing Testicular Immune Regulation: The Relationship between Sertoli Cells, Complement, and the Immune Response. Int. J. Mol. Sci. 2023, 24, 3371. https://doi.org/10.3390/ijms24043371
Washburn RL, Dufour JM. Complementing Testicular Immune Regulation: The Relationship between Sertoli Cells, Complement, and the Immune Response. International Journal of Molecular Sciences. 2023; 24(4):3371. https://doi.org/10.3390/ijms24043371
Chicago/Turabian StyleWashburn, Rachel L., and Jannette M. Dufour. 2023. "Complementing Testicular Immune Regulation: The Relationship between Sertoli Cells, Complement, and the Immune Response" International Journal of Molecular Sciences 24, no. 4: 3371. https://doi.org/10.3390/ijms24043371