Rosacea, Brain Cooling and Niacin Flush

Other players include:  Cathelicidins, Prostaglandins, Cryptic Bacteria, Nerves, Gut

What does it take to make your face red?  Excessive solar exposure can lead to apoptosis of skin cells overloaded with DNA damage and trigger inflammation: vasodilation, recruitment of neutrophils, swelling, etc.  Similarly, a local infection can cause inflammation and the accumulation of neutrophils (see The Inner Life/Extravasation for slide show), lymphocytes, etc., that is observed as pus.  These are general responses that occur in skin anywhere, but the face also blushes in response to emotional cues and flushes with exercise.  Rosacea seems to involve all of these reactions to produce a variety of symptoms of wide severity.  Here I try to provide an overview of the complex physiological interactions involved in rosacea.

Rosacea is Persistent Vasodilation of the Face with Accumulation of Neutrophils

The nervous and circulatory systems of the face are unique and provide numerous triggers for inflammation.  Emotional blushing is a common trait among those who progress to rosacea, even though this type of vasodilation is not easily observed with some facial characteristics.  Thus, many rosaceans claim to have never flushed before their first outbreak, but tests of skin circulation indicate that these individuals had skin types that prohibited display of the blushing.  The face is also adapted to control brain temperature, so changes in body temperature, physical activity, etc. can also trigger flushing.

Facial Blood Circulation to Cool the Brain

The cooling of the blood as it traverses the facial skin is used to cool the brain during extensive exercise or in warm environments.  This unique adaptation also means that control of facial vasodilation can potentially be disrupted in disease and cause symptoms of pathology.  In rosacea,  the brain cooling response is disturbed (see reference below), resulting in persistent vasodilation and suggesting that the unique control of inflammation in the face is why rosacea is limited to the face.  The pattern of blood circulation in the face, however, only roughly approximates the inflammation pattern in rosacea.

Nerves to the Face

The face receives sensory branching from the trigeminal nerve.  The enervation pattern of the branches matches emotional blushing, but they also appear to approximate the pattern of reddening in rosacea.  It makes sense that rosacea involves nerve-triggered dilation of the blood vessels of the face.  One contrast between emotional blushing and rosacea is that emotional blushing does not lead to the offloading of lymphocytes, whereas rosacea produces localization of neutrophils that exacerbate and prolong inflammation.

Cathelicidin, Vitamin D Receptor, DNA Complexes, Autoinflammation

A major component of the innate immune system is the group of basic antimicrobial peptides, cathelicidins.  Cathelicidins are effective against bacteria and they are produced during inflammation and are partially controlled by the vitamin D receptor acting as a transcription factor.  Thus, part of the action of vitamin D in providing protection against disease is by enhancing cathelicidin production.  Cathelicidin action in the skin parallels the control of intestinal villi development by defensins, that are also basic antimicrobial peptides under the control of vitamin D.  Cathelicidins also form complexes with host DNA from damaged cells.  These cathelicin/DNA complexes bind to toll-like receptors (TLRs) and trigger inflammation.  This reaction has been associated with psoriasis and may explain how neutrophil damage can perpetuate inflammation in rosacea.

Niacin Flushing Implicates Arrestins

The unique circulatory system of the face also makes it susceptible to flushing with niacin, a.k.a. nicotinic acid or vitamin B3.  Niacin is cheaper and much more effective at raising HDL and lowering triglycerides and LDL than statins, but is not fully utilized because it also produces intense facial flushes.  A recent article (below) has demonstrated that the lipid benefits can be separated from the flushing and implicated beta-arrestin 1 activation by niacin binding to GPR109A (G-protein-coupled receptor) as the triggering event.  Arrestin, which is involved in clathrin-mediated endocytosis, activates phospholipase A2 that in turn releases arachidonic acid (ARA) from phospholipids.  The ARA (that got into the phospholipids as the omega-6 fatty acid in vegetable oils) is converted by COX-2 into the inflammatory prostaglandin D2.  This prostaglandin is what stimulates vasodilation.  It is possible to produce chemicals that will stimulate the lipid metabolism alterations of niacin, without producing the arrestin activation and inflammation.  Aspirin can be used to inhibit COX-2 and other parts of NFkB-mediated inflammation and eliminate the niacin flush.  It is also interesting that the modified lipid metabolism of schizophrenics also eliminates niacin flushing.  Salicylic acid, the same as the acetylsalicylic acid of Aspirin without the acetate, is also used in some topical applications to quiet the symptoms of rosacea.  Arrestin activation may be involved in rosacea.

Gut Flora, Biofilms and Cryptic Bacteria

The gut is probably involved in most cases of rosacea and bacteria are also implicated by the modification of rosacea symptoms by antibiotics.  This area has not been explored, but I suspect that gut flora controlled by diet, as well as pathogenic biofilms and cryptic bacteria, e.g. Clamydia pneumoneae, in facial tissue are involved in varying degrees in the panoply of pathologies called collectively, rosacea.  Since the bacteria in contact with the gut determine the development of the lymphocytes in the lining of the gut, e.g. Tregs vs. T cells that fight infections, pathogenic gut biofilms may disrupt the normal function of the immune system and support rosacea.  Die off and release of cell wall endotoxin from cryptic bacteria could explain the paradoxical inflammation in response to many treatments that are normally anti-inflammatory.  I have discussed in another article potential approaches to strip off biofilms.

Treatment with Anti-Inflammatory Diet

The Anti-Inflammatory Diet (AID) and Lifestyle that I advocate on this blog would seem to be a natural cure for rosacea.  It should eliminate the inflammatory background that supports rosacea and was probably essential for its development.  This diet also eliminates acne, which is directly related to the accumulation of lymphocytes to make pus.  Inflammation is also needed for the offloading of neutrophils that exacerbate inflammation in rosacea.  Vitamin D is instrumental in cathelicidin production to eliminate cryptic bacteria. 

In most cases of rosacea, the AID should be helpful.  Eliminating dietary sources of inflammation, especially vegetable oils (the source of omega-6 fatty acids that are converted into inflammatory prostaglandins), should reduce rosacea symptoms.

In advanced, severe cases, however, it appears that maintenance of the suppression of the response to cryptic bacteria is required to prevent endotoxin-based inflammation.  Thus, most treatments that decrease inflammation, e.g. omega-3 oils, vitamin D3, Vagal maneuvers, can paradoxically produce elevated inflammation.  These treatments may also inadvertantly contribute to inflammation by upsetting pathogenic interactions between bacteria and intestinal cells.  I have discussed these paradoxical ramifications in another article.

references:
Brinnel H, Friedel J, Caputa M, Cabanac M, Grosshans E.  1989.  Rosacea: disturbed defense against brain overheating.  Arch Dermatol Res. 281(1):66-72.
Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ.  2009.  Beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.  J Clin Invest. 119(5):1312-21.