Nakagawa Yukinobu, Gallo Richard L
Division of Dermatology, University of California, San Diego, San Diego, CA 92161.
Division of Dermatology, University of California, San Diego, San Diego, CA 92161
J Immunol. 2015 Feb 1;194(3):1274-84. doi: 10.4049/jimmunol.1402388. Epub 2014 Dec 29.
Cathelicidins are a gene family best known for their antimicrobial action, but the diverse mature peptides they encode also have other host defense functions. The human cathelicidin peptide LL-37 enhances recognition of nucleic acids, an action whose significance is seen in human diseases such as psoriasis where it is associated with increased type 1 IFN production. This function has been attributed to the extracellular action of the peptide to facilitate uptake of nucleic acids. In this study, we demonstrate that the murine mature cathelicidin peptide (CRAMP), encoded by the mouse gene (Camp), is functionally distinct from the human mature peptide (LL-37), as it does not facilitate CpG entry. However, mouse cathelicidin does influence recognition of CpG as bone marrow-derived dendritic cells from Camp(-/-) mice have impaired CpG responses and Camp(-/-) mice had impaired response to CpG given i.v. or s.c. We show that cathelicidin concentrates in Lamp1 positive compartments, is colocalized with CpG in the endolysosome, can be immunoprecipitated with TLR9, and binds to CpG intracellulary. Collectively, these results indicate that the functions of cathelicidin in control of TLR9 activation may include both intracellular and extracellular effects.
猫抗菌肽是一个基因家族，以其抗菌作用而闻名，但它们编码的多种成熟肽也具有其他宿主防御功能。人猫抗菌肽LL-37可增强对核酸的识别，这种作用在诸如银屑病等人类疾病中具有重要意义，在这些疾病中它与1型干扰素产生增加有关。该功能归因于该肽的细胞外作用以促进核酸摄取。在本研究中，我们证明由小鼠基因（Camp）编码的鼠成熟猫抗菌肽（CRAMP）在功能上与人成熟肽（LL-37）不同，因为它不促进CpG进入。然而，小鼠猫抗菌肽确实影响对CpG的识别，因为来自Camp（-/-）小鼠的骨髓来源的树突状细胞具有受损的CpG反应，并且Camp（-/-）小鼠对静脉内或皮下给予的CpG反应受损。我们表明，猫抗菌肽集中在Lamp1阳性区室，在内溶酶体中与CpG共定位，可与TLR9进行免疫沉淀，并在细胞内与CpG结合。总体而言，这些结果表明猫抗菌肽在控制TLR9激活中的功能可能包括细胞内和细胞外效应。
