Lipid-based signaling

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that is highly concentrated in the brain, making up about 10–20% of the total lipids (1).  DHA is released from the action of Ca2+-independent iPLA2 and is then converted into oxylipins, including resolvins and neuroprotectins, which are involved in physiological processes like cellular homeostasis, inflammation, immunity and vascular functions. (2)

DHA plays a significant role in brain development and function, neuronal function, fetal development, cardiovascular functioning, eye health and more. Hence, abnormal DHA signaling is implicated in many diseases, including neuropsychiatric disorders and cardiovascular diseases.

The neuroprotective function of DHA is due to multiple mechanisms. For instance, DHA supports neuronal survival by stimulating the induction of cAMP response element-binding (CREB) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways, which regulate neuronal plasticity, development, activation, long-term memory and other neuronal functions. DHA also reduces caspase-3 and caspase-8 activity to inhibit apoptosis in neuronal cells and preserve neuronal integrity under oxidative stress conditions (3).

DHA contributes to neural morphology by activating the retinoid X receptor (RXR) and the G-protein coupled receptor GPR40/FFAR1. This activation then increases intracellular calcium via multiple mechanisms to activate the CREB pathway, which then leads to the expression of antiapoptotic and neuroprotective genes such as Bcl-2, influencing neuronal survival (4).

DHA supports synaptic function by promoting communication through the induction of synaptic proteins, like postsynaptic receptors, consisting of α and β-type receptors or scaffolding proteins like Bcl2.

DHA can also protect neuronal health when converted to neuroprotective lipid mediators oxylipins, including resolvins and neuroprotectins, which are specific types of oxylipins. Additionally, DHA can undergo lipid oxidation and create oxylipin metabolites that help regulate oxidative cell homeostasis by influencing transcription factors, such as NF-κB and Nrf2, which are also involved in neuroprotection (5).

Lower DHA levels are linked to normal brain aging in older healthy adults and are also seen in patients with neurodegenerative conditions like Alzheimer’s disease. Studies have shown that having more DHA in diets reduces the risk of developing cognitive problems. 

DHA signaling and its effects on neurodevelopment and neuroprotection involve membrane and metabolite-mediated signal transduction mechanisms that include interactions with proteins like membrane-bound receptors, ion channels and enzymes. For instance, DHA stimulates the synthesis of neuronal phosphatidylserine (PS), leading to DHA-PS-rich membrane domains that activate proteins, including Raf-1, protein kinase C (PKC) and Akt, promoting neuronal development and survival (6).

DHA is metabolized in neural tissues to produce bioactive mediators such as neuroprotectin D1, which has anti-inflammatory and antioxidant effects. Another lipid mediator synthesized from the DHA, synaptamide, is anti-inflammatory and promotes neurogenesis and synaptogenesis. 

Eicosanoids are lipid signaling molecules derived from 20-carbon polyunsaturated fatty acids, with arachidonic acid being the most common source. The eicosanoids consist of prostaglandins (PG), thromboxanes (TX), leukotrienes (LT) and lipoxins (LX) (7). Eicosanoids regulate biological processes like inflammation, platelet aggregation, tissue homeostasis, host defense, bronchoconstriction, bronchodilation, vascular permeability and smooth muscle contraction. They typically act on the cells that produce them or on nearby cells. For instance, eicosanoids regulate T lymphocyte function by signaling through their receptors on the surface of T cells. As a result, they are described as local hormones acting through autocrine or paracrine signaling (8).

Eicosanoids are also implicated in pathophysiological processes associated with conditions like cardiovascular diseases, hypertension, autoimmune conditions and cancer.

Eicosanoids can either promote or reduce inflammation, depending on the cellular environment, the eicosanoid receptor present and the duration of inflammation (9,10).

Eicosanoid inflammatory mediators like prostaglandins E2 (PGE2) contribute to inflammatory symptoms by promoting arterial dilatation, increasing microvascular permeability and increasing blood flow into the affected tissue to cause redness and swelling (11).

Prostaglandin D2 (PGD2) can act through its receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) to induce cytokine production and immune cell migration during helminth‐ and allergen‐induced Type 2 inflammation. It may also inhibit inflammation by activating the DP1 receptor to prevent dendritic cell migration from the lung to lymph nodes, decreasing proliferation and cytokine production by antigen-specific T cells (12).

Targeting eicosanoid pathways has therapeutic applications in treating inflammatory diseases, including pain and asthma. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase enzymes, which convert arachidonic acid into thromboxanes, prostaglandins and prostacyclins, managing inflammation (13). Leukotriene inhibitors are used in managing asthma because they inhibit cysteinyl leukotriene receptor 1 (cysLT1) activity, preventing, for example, bronchoconstriction during lung inflammation (14).

Although therapies targeting eicosanoids have improved the treatment of inflammatory symptoms like swelling and pain, eicosanoid inhibition has little effect on chronic and life-threatening diseases such as arthritis and atherosclerosis (15).

Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator that signals by binding to its G protein-coupled S1P receptors. It regulates cellular processes such as cell-cell and cell-matrix adhesion, cell migration, growth, differentiation, death and survival. It also regulates other physiological processes, including inflammation, vascular development, central nervous system homeostasis, immunity and tumorigenesis. Dysregulated  S1P signaling is associated with cancer, nervous system diseases, cardiovascular diseases, respiratory diseases and more, making it a valuable therapeutic target for these diseases. Therapy targeting S1P signaling is currently available in treating relapsing-remitting multiple sclerosis. 

S1P receptor activation can trigger lymphocytes and other immune cells to migrate. Specifically, S1P controls the exit of lymphocytes from lymph nodes into the bloodstream, which follow an S1P gradient. Additionally, S1P signaling is involved in retaining immune cells and positioning them within lymphoid tissues (16).

S1P signaling is pivotal to pathological processes associated with autoimmune diseases, cancer and cardiovascular conditions, which has significant implications for the treatment of these diseases.

In treatments for autoimmune diseases such as multiple sclerosis, S1P signaling is targeted to prevent lymphocytes from migrating from the lymph nodes into inflammation sites, thereby reducing inflammation and autoimmunity. S1P receptor modulators, like fingolimod, siponimod, ozanimod and ponesimod, are currently approved for treating multiple sclerosis and more are being studied for treating other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and psoriasis (17).

In cancer, S1P signaling promotes cancer cell growth, metastasis, survival and immune tolerance to the tumor microenvironment. S1PR1 signaling can also trigger the activation of other signaling pathways involved in carcinogenesis, including PI3K/AKT, MAPK/ERK1/2, Rac and PKC/Ca. Modulating S1P signaling can disrupt processes involved in cancer progression, making S1PR signaling a potential anti-tumor therapeutic target (18).

SIP signaling regulates cardiovascular-related functions, including endothelial function, cardiac contractility,  cardiac homeostasis and vascular tone, by binding and activating S1PR1, S1PR2 and S1PR3 expressed in endothelial and smooth muscle cells, cardiomyocytes and fibroblasts. Dysregulated S1P signaling is implicated in cardiovascular diseases, including arterial hypertension and atherosclerosis. Selective S1P receptor modulators are being investigated to promote protective cardiovascular effects while minimizing adverse outcomes (19).