LL-37 Immunomodulatory Activity during Mycobacterium tuberculosis Infection in Macrophages

Abstract

Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to a great extent on the innate immune response against mycobacteria. Host defense peptides (HDP) are one of the first barriers to counteract infection. Cathelicidin (LL-37) is an HDP that has many immunomodulatory effects besides its weak antimicrobial activity. Despite advances in the study of the innate immune response in tuberculosis, the immunological role of LL-37 during M. tuberculosis infection has not been clarified. Monocyte-derived macrophages were infected with M. tuberculosis strain H37Rv and then treated with 1, 5, or 15 g/ml of exogenous LL-37 for 4, 8, and 24 h. Exogenous LL-37 decreased tumor necrosis factor alpha (TNF-␣) and interleukin-17 (IL-17) while inducing anti-inflammatory IL-10 and transforming growth factor ␤ (TGF-␤) production. Interestingly, the decreased production of anti-inflammatory cytokines did not reduce antimycobacterial activity. These results are consistent with the concept that LL-37 can modulate the expression of cytokines during mycobacterial infection and this activity was independent of the P2X7 receptor. Thus, LL-37 modulates the response of macrophages during infection, controlling the expression of proinflammatory and anti-inflammatory cytokines.T uberculosis (TB), caused by Mycobacterium tuberculosis, is the single deadliest communicable disease. In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease (1).The main cells involved in the control of tuberculosis are macrophages, and together with epithelial cells, they are the first antiinfective immunological barriers encountered, with a primary task to initiate pathogen clearance. In the progress of cellular immunity against M. tuberculosis, macrophages can also function as antigen-presenting cells, in which the antigens of M. tuberculosis are degraded into immunogenic polypeptides and presented on T lymphocytes by the major histocompatibility complex to trigger adaptive immunity. However, M. tuberculosis has developed a wide assortment of strategies to counteract the bactericidal activities of these cells, enabling it to successfully establish a niche for long-term survival within macrophages. This M. tuberculosis replication causes mild inflammation, which promotes cell-mediated immunity that often leads to M. tuberculosis retention through granuloma (tubercle) formation (2). When infection becomes reactivated at a low rate, the granuloma suffers caseous necrosis, and this results in lung cavitation and pulmonary disease, inducing a prominent inflammation (3). Several molecules of the immune system are involved throughout this process, including host defense peptides (HDP) such as cathelicidin and defensins (4-6).LL-37 is the unique member of cathelicidin family in humans; this multifunctional immunomodulatory HDP is produced mainly by phagocytic leukocytes and epithelial cells as well as being normally found at concentrations varying from 2 to 5 g/ml in several fl...

Immunomodulatory effects of anti-microbial peptides

“…Exogenous LL-37 decreases TNF-α and IL-17 while inducing antiinflammatory IL-10 and TGF-β production in a monocyte-derived macrophage cell line infected with Mycobacterium tuberculosis [82]. However, the decreased production of anti-inflammatory cytokines does not reduce anti-mycobacterial activity supporting the concept that LL-37 modulation of cytokines is independent of the P2X7 receptor.…”

The effects of first-line anti-tuberculosis drugs on the actions of vitamin D in human macrophages

“…Several studies have confirmed that vitamin D induces hCAP18 expression in cultured human macrophages [21], [24], [31], [32]. However many clinical studies have failed to show a positive effect of vitamin D on the treatment of tuberculosis infection [33].…”

Expression and Function of Host Defense Peptides at Inflammation Sites

“…Accordingly, a recent study investigated the therapeutic potential of LL-37 in modulating macrophage-mediated excessive inflammatory responses. It was found that LL-37 reduced the severity of tuberculosis by rapidly enhancing the anti-inflammatory cytokine TGF-β, IL-10, and prostaglandin E from the infected macrophages [128]. However, further studies regarding the exogenous effect of LL-37 in severe pulmonary tuberculosis are warranted.…”