Endogenous Anti-Inflammatory Neuropeptides and Proresolving Lipid Mediators: A New Therapeutic Approach for Immune Disorders

This is a review article that I found interesting given the fact that at the Barbara Davis Center I hear a lot of talks about autoimmune disease. The paper discussed factors affecting the balance between pro-inflammatory and anti-inflammatory signals in the body, including regulatory T cells and T cell effectors. Mainly discussed were the regulatory abilities of endogenous neuropeptides (such as vasoactive intestinal peptide, α-melanocyte stimulating hormone, urocortin, adrenomedullin, cortistatin and ghrelin) and lipid mediators (omega-3 and omega-6 polyunsaturated fatty acids--PUFAs).

Endogenous neuropeptides have been observed to do the following:
1. Counterbalance inflammatory response
2. Downregulate Th1 response
3. Generate regulatory T cells (Tregs)

What especially caught my eye during my reading about the neuropeptides is that they induce the peripheral expansion of antigen-specific Tregs, which have a suppressive activity on self-reactive T cells. The suppressive mechanism of Tregs is mainly dependent on cytotoxic T-lymphocyte-associated protein 4 (CTLA4), or through production of immunosuppressive cytokines. Trialnet, the large diabetes prevention/amelioration study which I participate in (doing HLA typing) has a CTLA4 study going on using the drug Abatacept, which is a fusion protein of the extracellular domain of CTLA4 bound to immunoglobulin. Abatacept prevents T cells from getting activated when the CTLA4 domain binds to B7 on the antigen presenting cell. If the B7 is bound by the CTLA4 domain, then CD28 on the T cell cannot bind B7 and receive the costimulation necessary to activate the T cell. The drug Abatacept is currently approved for the treatment of Rheumatoid Arthritis.

Omega-3 and Omega-6 PUFAs are precursors for tons of different molecules, both pro-and anti-inflammatory. Some of the molecules Omega-6 PUFAs make are prostaglandins and leukotrienes, which are strongly pro-inflammatory molecules. I had been under the impression that Omega-6 PUFAs were exclusively pro-inflammatory, but according to this review, they can also stimulate pathways that lead to inflammation resolution. I have read some material that indicates the American diet has a too high Omega-6 to Omega-3 PUFA ratio which ruins our health (heart disease, cancer, etc.) So I was surprised to find that it is possible for them to aid inflammation resolution as well. I wonder if there is a way to make Omega-6 PUFAs be anti- rather than pro-inflammatory?

The article concluded with some analysis on how these molecules could be developed into novel therapeutics. Some have been successfully tested in animal models. Advantages of these molecules include that fact that they have a wide spectrum of action in vivo. However, neuropeptides are extremely unstable and side effects of most of the molecules are unknown. For example, I recently found out that ghrelin is involved in hunger and satiety, so would use of this neuropeptide therapeutically affect patient weight? I’m sure there are many such questions that could only be answered with animal experiments and clinical trials. In view of other natural human compounds that have been found to be therapeutic such as insulin and cortisone, these substances may present an attractive therapeutic option, but as usual, much work needs to be done.

Resource: Anderson, P., Delgado, M. ENDOGENOUS ANTI-INFLAMMATORY NEUROPEPTIDES AND PRORESOLVING LIPID MEDIATORS: A NEW THERAPEUTIC APPROACH FOR IMMUNE DISORDERS.
J Cell Mol Med. 2008 Jun 12. [Epub ahead of print]