Heparin and Inflammation

Heparin dominates the extracellular world and controls inflammation

Why is heparin such a big deal in inflammation? Heparin controls the communication between cells and to a great extent it also controls what goes in and out of cells. At the same time there appears to be a feedback system, so that cells that have their inflammation program triggered also change their production of heparin.

I am using the term “heparin” very loosely here to include all of the different forms of the highly sulfated polysaccharide. All of these different forms start as polysaccharides (long sugar chains) extending from proteins, i.e. proteo (protein) glycans (polysaccharides). The sugar chains are made by enzymes that alternately add a negatively charged sugar (glucuronic acid) and then a positively charged sugar (N-acetylglucosamine) in long chains to a four sugar linker attached to a protein. The “heparan” polysaccharide is then altered chemically and highly negatively charged sulfate groups are added. The alterations are not uniform along the length of the heparan, but rather form islands along the chains with special structures. In some cells, the long heparan sulfate chains are attacked by enzymes, so that the heavily sulfated islands are released as short chains, oligosaccharides, called heparin. Heparin is commonly secreted by mast cells as these cells secrete their companion molecule histamine during responses to allergens. Thus, one function of heparin, which is negatively charged, is to neutralize the positive charge on histamine as they are stored in vesicles prior to release.

Heparan sulfate proteoglycans (HSPGs) are continually secreted and then brought back into cells. This turnover is fairly rapid, so the HSPGs that dominate the surface of cells is renewed every six hours. This is true for most cells, including your cartilage cells, chondrocytes, that live in small HSPG-lined capsules within the cartilage (collagen fibers in another sulfated polysaccharide, chondroitin sulfate) as they mine the cartilage as their source of protein and carbohydrates at one end of the cell and synthesize new cartilage from the other end. Damaged cartilage must be pressed very firmly together, so that these chondrocytes can knit the damaged regions back together with their burrowing/synthesis action. At the same time that cartilage protein fibers and polysaccharides are being recycled on a tissue-wide scale (collagens have a lifetime of at least decades), the cells rapidly treadmill their HSPGs.

Some proteins travel on the HSPGs from one cell, to adjacent cells. The HIV protein called TAT is secreted from HIV-infected cells bound to HSPG. As the bound TAT is swept from one end of the cell to another, it encounters the HSPGs sweeping over the surface of neighboring cells and jumps ship, so to speak. The TAT is then swept into the unsuspecting neighbor that has not previously experienced HIV. The particular heparin-binding regions of the TAT protein are similar to the nucleic acid-binding regions of cellular proteins, so the TAT is transported to and into the nucleus, where the TAT acts as a transcription factor and prepares the cell for HIV infection.

Heparan sulfates dominate the extracellular region surrounding a cell and the heparan sulfate chains attach to both hormones and hormone receptors and mediate signaling. For example, the inflammatory and anti-inflammatory cytokines and their receptor proteins embedded in the cell surface all have heparin-binding domains. Heparin-binding domains are also present in proteins of the clotting system, most of the complement components and in many of the proteins that regulate development. Most defensive peptides with antimicrobial properties have heparin-binding domains and if heparin binding domains are removed from proteins, they are antimicrobial peptides.

Heparan sulfate proteoglycans dominate the extracellular interactions the way nucleic acids dominate the nucleus. Phospholipids and inositol phosphates may be similarly dominant in the cytoplasm. It is interesting that the active component in digestive fiber is inositol hexaphosphate, phytic acid. Also note that amyloid diseases, such as Alzheimer’s and type I diabetes are characterized by extracellular fiberous aggregates of proteins, e.g. beta-amyloid, on a scaffold of heparin. Some of the amyloid proteins don’t have heparin-binding domains, until they stack into fibers. The cellular scaffold for tau fibers has not yet been identified, but perhaps it is a form of polymerized inositol phosphate.

Many drugs act on heparin-binding or interacting domains and that is another reason why heparin and heparin-binding are critical elements of inflammation.