Multifunctional Roles of Human Cathelicidin (LL-37) at the Ocular Surface

Abstract

LL-37 expression is upregulated in regenerating human corneal epithelium, has antibacterial activity against ocular pathogens under physiologically relevant conditions, and stimulates HCEC migration and cytokine production. These findings suggest that LL-37 acts as a multifunctional mediator that helps protect the cornea from infection and modulates wound healing.

Cathelicidin-Deficient (Cnlp−/−) Mice Show Increased Susceptibility toPseudomonas aeruginosaKeratitis

“…19 This ATCC strain is known to produce severe ocular infection in experimentally infected animal models of bacterial keratitis. 40,41 PA cultures were suspended in phosphate buffer (PB) to a concentration of 2.0 × 10 8 cfu/mL.…”

“…Further, the vessel growth observed in the KO mice could have been initiated by the higher number of infiltrating neutrophils and possibly macrophages, as these cells contain significant amounts of angiogenic mediators that can be released in response to cellular activation. [65][66][67] Notably, the ability of cytokines to induce other cytokines and pro-and/or antiangiogenic factors secondarily and function as chemotactic factors for inflammatory cells makes it difficult to sort out the final and critical mediators of angiogenesis, infiltration, and inflammation conclusively in vivo.In the cornea, epithelial cells are a source of various antimicrobial peptides (including CRAMP, data not shown), particularly after injury or in response to inflammatory 19,[68][69][70] Furthermore, infiltrating neutrophils and macrophages present in the cornea as a result of microbial challenge also play an important role in limiting bacterial invasion by the production of certain peptides including the cathelicidins. Findings from the present study showed that functional activities of cathelicidin are necessary for bacterial clearance and innate corneal immunity at the ocular surface.…”

“…11 In keeping with their role in host innate immunity providing the first line of defense against microbial infection, cathelicidins have been identified in leukocytes such as neutrophils and macrophages, 12,13 skin epidermis, [14][15][16] and epithelial surfaces of various tissues including that of the ocular surface. [17][18][19][20][21] The mechanism of action by which cathelicidins exert their antimicrobial effects is through disruption of the anionic microbial membrane by electrostatic interaction resulting in cell permeabilization and death. 22 In addition to being antimicrobial, cathelicidins are increasingly known to be multifunctional, regulating processes unrelated to microbial killing, such as the ability to chemoattract cells of the innate and adaptive immune systems including neutrophils, mast cells, monocytes and T-lymphocytes.…”

“…39 We have reported that LL-37 is a potent antimicrobial effective against various ocular pathogens. 18 Furthermore, LL-37 is capable of stimulating cell migration and modulating chemokine and cytokine production by corneal epithelial cells 19 which suggest that LL-37 may act as a multifunctional mediator and play an important part in stimulating the innate immune response in the cornea. Although our in vitro studies support a physiological role for cathelicidin (LL-37) in ocular innate immunity, there have been no studies addressing this directly in vivo.…”

Impairment of Angiogenic Activity in the Serum From Patients With Coronary Aneurysms Due to Kawasaki Disease

“…16 Briefly, HUVEC were grown in a 25 cm 2 tissue culture flask (Asahi Technoglass) until they were approximately 80% confluent. The cells were then trypsinized, washed, counted, and resuspended in serum-free and growth factorfree EBM-2 basal medium.…”