Psoriasis & Psoriatic Arthritis

Psoriasis and bacterial activation of TLRs and NFkB—Toll-like receptors in skin (Adv Dermatol 2008[1]): The author cites research showing that keratinocytes in psoriatic lesions have increased levels of TLRs 1, 2, 4, 5 and 9 compared with normal skin; this suggests the probability of enhanced responsiveness to microbial immunogens. Whether this upregulated expression of TLRs is a nonspecific response to inflammation or a specific response to the presence of microorganisms is not clear; however what is very obvious is that the presence of microbe-sensing TLRs with the presence of additional bacteria on the skin of psoriatic paitents certainly provides a well-set stage for dermatologic inflammation. “Thus,” the author notes, “TLR activation may also play a role in the pathophysiology of psoriasis by exacerbating the disease process.” Also noted is the very important observation that the antimicrobial peptide cathelicidin (LL-37), which is found at high levels in psoriatic skin, can convert non-stimulatory self-DNA into a potent activator of TLR-9 on dendritic cells (plasmacytoid DCs) resulting in production of IFN-alpha, leading to the conclusion that “This may be one important mechanism of how TLRs can promote autoimmunity in psoriasis.” Per review by Lamphier et al[2], TLR-9 is expressed intracellularly and is activated in response to DNA, in particular DNA containing unmethylated CpG motifs that are more prevalent in microbial than mammalian DNA; however, under certain conditions, TLR-9 can recognize self-DNA and this may promote immune responses against DNA such as noted in the autoimmune disease systemic lupus erythematosis (SLE) particularly as TLR-9 binds rather indiscriminately to a broad range of DNAs. Notice the implications and stream of probable events: microbe-induced skin inflammation and injury à upregulation of TLRs (esp. TLR-9) and antimicrobial peptides (esp. cathelicidin) à  cathelicidin-induced conversion of nonoffensive self-DNA into an autoinflammatory immunogen, which then potently activates the already upregulated TLR-9 = microbial inflammation results in autoimmunity/autoinflammation (to self-DNA).  A well-known function of TLRs is, via their transmembrane domain and a cytoplasmic tail domain that is homologous to the interleukin-1 receptor, the initiation of various intracellular signaling cascades, including activation of nuclear factor-kB (NFkB), which is a key transcription factor that promotes transcription of genes coding for pro-inflammatory molecules such as cytokines, chemokines, co-stimulatory molecules (needed for immune responsiveness), and adhesion molecules (needed for the homing of immunocytes to inflamed/damaged tissue)