Scavenger receptor (immunology)

Scavenger receptors are a large and diverse superfamily of cell surface receptors. Its properties were first recorded in 1970 by Drs. Brown and Goldstein, with the defining property being the ability to bind and remove modified low density lipoproteins (LDL).[1] Today scavenger receptors are known to be involved in a wide range of processes, such as: homeostasis, apoptosis, inflammatory diseases and pathogen clearance. Scavenger receptors are mainly found on myeloid cells and other cells that bind to numerous ligands, primarily endogenous and modified host-molecules together with pathogen-associated molecular patterns(PAMPs), and remove them.[2] The Kupffer cells in the liver are particularly rich in scavenger receptors, includes SR-A I, SR-A II, and MARCO.[3]

Not to be confused with Scavenger receptor (endocrinology).
Scavenger receptor
Identifiers
SymbolScavenger receptor
OPM superfamily456
OPM protein5ktf
Membranome4

Function

The scavenger receptor superfamily is defined by its ability to recognize and bind a broad range of common ligands. These ligands include: polyanionic ligands including lipoproteins, apoptotic cells, cholesterol ester, phospholipids, proteoglycans, ferritin, and carbohydrates.[4] This broad recognition range allows scavenger receptors to play an important role in homeostasis and the combating of diseases. This is accomplished via the recognition of various PAMP's and DAMP's, which leads to the removal or scavenging of pathogens with the recognition of PAMP's and the removal of apoptotic cells, self reactive antigens and the products of oxidative stress.

In atherosclerotic lesions, macrophages that express scavenger receptors on their plasma membrane take up the oxidized LDL deposited in the blood vessel wall aggressively, and develop into foam cells. Likewise, they secrete various inflammatory cytokines and accelerate the development of atherosclerosis.

Types
Schematic collection of the scavenger receptor superfamily. Classes A-J are displayed with their respective domains. All classes have a mammalian orthologue, with the exception of C.

Scavenger receptors are incredibly diverse and therefore, organized into many different classes, starting at A and continuing to L.[2] This organization is based on their structural properties. Due to the diversity and ongoing research into scavenger receptors, the receptors lack an accepted nomenclature and have been described under different names. In 2014 a new nomenclature[5] was proposed that has been used by some researchers, although no official recognition has been given.[6][4]

Class A

Class A receptors are a type II membrane protein who use their collagen-like domain for ligand binding.

Members include:Scavenger receptors type 1 (SR-A1), which is a trimer with a molecular weight of about 220-250 kDa (the molecular weight of monomeric protein is about 80 kDa). It preferentially binds modified LDL, either acylated (acLDL) or oxidized (oxLDL). Other ligands include: β-amyloid, heat shock proteins, surface molecules of Gram-positive and Gram-negative bacteria, hepatitis C virus.

SR-A1 can be alternatively spliced to generate a truncation at the C-terminus; it is contained within the Endoplasmatic Reticulum, and just like the unspliced version, has a strong affinity for polyanionic ligand binding.

  • SCARA1 or MSR1 (SR-A1): besides macrophages they can be found on smooth vascular muscle cells and endothelial tissues; oxidative stress enhances their presence on the endothelium.
  • SCARA2 or MARCO (SR-A6): only found on macrophages in the peritoneum, lymph nodes, liver and specific zones of the spleen. Bacteria and lipopolysaccharide produced by bacteria stimulate its expression; SR-A6 is unable to connect with modified LDL.
  • SCARA3, MSRL1 or APC7 (SR-A3): plays a significant role in the protection against reactive oxygen species (ROS).
  • SCARA4 or COLEC12 (SR-A4): acts as a receptor for the detection, engulfment and destruction of oxidatively modified LDL for vascular endothelial cells.
  • SCARA5 or TESR (SR-A5): located in a diverse set of tissues, such as, lung placenta, intestine, heart and epithelial cells, it has a high affinity for bacteria but not for modified LDL.

Class B

CD36 and scavenger receptor class BI are identified as genes encoding for oxidized LDL receptors and classified into scavenger receptor B (SR-B). Both proteins have two transmembrane domains with an extracellular loop, and they are concentrated in a specific plasma membrane microdomain, the caveolae.

Members include:

  • SCARB1 or CD36L1 (SR-B1): can interact not only with oxidized LDL but also with normal LDL and high-density lipoproteins (HDL), and plays an important role in their transportation into the cells. Recent studies have indicated that SR-B1 is likely to be the major receptor involved in HDL metabolism in mice and humans.[8][9] Besides LDL and HDL, SR-B1 binds to viruses and bacteria. SR-B1 is located on hepatocytes, steroidogenic cells, arterial wall and macrophages. Mutations in SR-B1 have a negative effect on fertility and innate immune response, and leads to an increase in atherosclerosis.
  • SCARB2
  • SCARB3 or CD36 (SR-B2): has been thought to be implicated in cell adhesion, developmment of blood vessels, in the phagocytosis of apoptotic cells, and in the metabolism of long-chain fatty acids. Furthermore, it has been shown that CD36 is heavily involved with macrophage migration and signalling, together with protecting the host against, bacteria, fungi and malaria parasites. In experimental mice models of atherosclerosis, in which the gene for CD36 has been deleted, the mice have a greatly reduced number of atherosclerotic lesions.[10] CD36 can be found in many different cells, for example, insulin-responsive cells, hematopoietic cells like platelets, monocytes, and macrophages, endothelial cells, and specialized epithelial cells in the breast and the eye.

Other

Some receptors that can bind to oxidized LDL have been discovered.

References
  1. Patten DA, Shetty S (2018). "More Than Just a Removal Service: Scavenger Receptors in Leukocyte Trafficking". Frontiers in Immunology. 9: 2904. doi:10.3389/fimmu.2018.02904. PMC 6315190. PMID 30631321.
  2. PrabhuDas MR, Baldwin CL, Bollyky PL, Bowdish DM, Drickamer K, Febbraio M, et al. (May 2017). "A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease". Journal of Immunology. 198 (10): 3775–3789. doi:10.4049/jimmunol.1700373. PMC 5671342. PMID 28483986.
  3. Murphy K, Weaver C (2017). Janeway's immunobiology (Ninth ed.). New York, NY, USA. ISBN 978-0-8153-4505-3. OCLC 933586700.
  4. Zani IA, Stephen SL, Mughal NA, Russell D, Homer-Vanniasinkam S, Wheatcroft SB, Ponnambalam S (May 2015). "Scavenger receptor structure and function in health and disease". Cells. 4 (2): 178–201. doi:10.3390/cells4020178. PMC 4493455. PMID 26010753.
  5. Prabhudas M, Bowdish D, Drickamer K, Febbraio M, Herz J, Kobzik L, et al. (March 2014). "Standardizing scavenger receptor nomenclature". Journal of Immunology. 192 (5): 1997–2006. doi:10.4049/jimmunol.1490003. PMC 4238968. PMID 24563502.
  6. Pombinho R, Sousa S, Cabanes D (November 2018). "Scavenger Receptors: Promiscuous Players during Microbial Pathogenesis". Critical Reviews in Microbiology. 44 (6): 685–700. doi:10.1080/1040841X.2018.1493716. PMID 30318962.
  7. Matsumoto A, Naito M, Itakura H, Ikemoto S, Asaoka H, Hayakawa I, et al. (December 1990). "Human macrophage scavenger receptors: primary structure, expression, and localization in atherosclerotic lesions". Proceedings of the National Academy of Sciences of the United States of America. 87 (23): 9133–7. Bibcode:1990PNAS...87.9133M. doi:10.1073/pnas.87.23.9133. PMC 55118. PMID 2251254.
  8. Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M (November 1997). "A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12610–5. Bibcode:1997PNAS...9412610R. doi:10.1073/pnas.94.23.12610. PMC 25055. PMID 9356497.
  9. Khovidhunkit W (April 2011). "A genetic variant of the scavenger receptor BI in humans". The New England Journal of Medicine. 364 (14): 1375–6, author reply 1376. doi:10.1056/nejmc1101847. PMID 21470028.
  10. Kuchibhotla S, Vanegas D, Kennedy DJ, Guy E, Nimako G, Morton RE, Febbraio M (April 2008). "Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II". Cardiovascular Research. 78 (1): 185–96. doi:10.1093/cvr/cvm093. PMC 2810680. PMID 18065445.
  11. Mehta JL, Chen J, Hermonat PL, Romeo F, Novelli G (January 2006). "Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders". Cardiovascular Research. 69 (1): 36–45. doi:10.1016/j.cardiores.2005.09.006. PMID 16324688.
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