 |
By Prashant Kumar, PhD Candidate in Kizhakkedathu Lab, CBR |
Host defense peptides (HDP; also known as antimicrobial peptides) are short positively charged peptides produced by animals, insects and plants. Originally, these peptides were thought to only have direct antimicrobial activity against a broad range of microorganisms, such as bacteria, fungi and viruses. However, many new studies revealed that HDP also play an important role in immune modulation, wound healing, and diseases, such as cancer and autoimmune disorders. Recently, Dr. Evan Haney and Dr. Erin Gill from the Hancock Lab at the CBR published a review article in Nature Review summarizing the different functions of two human host defense peptides – cathlicidin LL-37 and defensins – and their relationship with various diseases.
Immunity and inflammation
Human cathelicidin LL-37 and defensins are expressed in many cell types, including epithelial and immune cells such as macrophages, monocytes, natural killer cells and neutrophils. Interestingly, these peptides elicit both pro and anti-inflammatory response depending on the cell type and stimuli. For example, LL-37 can induce histamine release from mast
Human defense peptides are now known to be involved in both direct microbial killing and immune modulation. Hancock, R. E et al. NatureBiotech. 2006, 24, 1551−7
cells, but produce an anti-inflammatory response in B-cells, and T cells. The peptides can also directly attract various immune cells.
Additionally, defensins have unique properties to activate platelets and promote stem cell migration in skin and intestinal epithelial cells. HDP influence multiple signaling pathways that are involved in immunity and inflammation, which may explain their wound healing ability. Early clinical trials with LL-37 have revealed an effective topical treatment for hard to treat venous leg ulcers.
Relationship between HDP and Disease
HDP expression is tightly controlled in the skin, lungs, gut and circulatory system. Dysregulation of many natural HDP correlates with disease onset and progression depending on the location. LL-37 is normally produced in sweat and mast cells of healthy skin but is overexpressed in the skin of patients with psoriasis. Atopic dermatitis and some skin infections are also related to LL-37 and defensins regulation.
In pulmonary diseases, such as cystic fibrosis, characterized by a mucus build up and colonization by S. aureus and Pseudomonas aeruginosa bacteria, synthetic HDP have shown therapeutic promise. They are able to directly target the bacterial infection and can dampen the hyper-inflammatory response.
Moreover, some studies illustrated that mice without the cathelicidin gene had tumors that grew faster and their NK cells had impaired activity against tumors. Counterintuitively, LL-37 was overexpressed in cancer cells and stimulated tumor growth and proliferation. Blocking the interaction between LL-37 and specific tumor cell receptors impaired tumor cell growth.
Similar to LL-37, increased levels of defensins in patients with cancer suggest that it might also promote tumor cell proliferation. However, it might also just reflect an aberrant host response. These studies show that there is much to be learned about the role of HDP in cancer.
HDP are complex signaling molecules that are involved in immunity, inflammation and different diseases. It should be emphasized that HDP do not act on specific signaling pathways in their effector cells and hence a systems biology approach is needed to fully understand the roles of HDP and identify novel therapeutics.