Tissue and Cell 45 (2013) 318–320 Contents lists available at SciVerse ScienceDirect Tissue and Cell j our nal homep a ge: www.elsevier.com/locate/tice Neutrophils LL-37 migrate to the nucleus during overwhelming infection Fabiano Pinheiro da Silva a,* , Maria Cristina Rodrigues Medeiros b , Ângela Batista Gomes dos Santos b , Marcelo Alves Ferreira c , Ana Lucia Garippo d , Roger Chammas e , Elia Caldini c , Irineu Tadeu Velasco a , Heraldo Possolo de Souza a , Marcel Cerqueira César Machado a a Emergency Medicine Department, University of São Paulo, Brazil b Pathology Department, University of São Paulo, Brazil c Cell Biology Department, University of São Paulo, Brazil d PREMIUM Confocal Microscopy Core Facility, University of São Paulo, Brazil e Oncology Department, University of São Paulo, Brazil a r t i c l e i n f o Article history: Received 20 November 2012 Received in revised form 8 April 2013 Accepted 23 April 2013 Available online 4 June 2013 Keywords: Antimicrobial peptides Sepsis Inflammation a b s t r a c t LL-37 is the only cathelicidin produced by human cells. It is secreted by a variety of cell types, includ- ing monocyte/macrophages, neutrophils, mast cells, keratinocytes and epithelial cells, acting on the extracellular milieu by directly killing bacteria or boosting innate immunity. Here, we show that LL- 37 translocates to the nucleus following overwhelming infection, putting in evidence that its role may be even broader, with new potential important implications to cell biology. Future studies are necessary to address if LL-37 is able to induce or affect transcription, since it can lead to a novel cell signaling pathway that probably will contribute to the understanding of complex diseases. © 2013 Elsevier Ltd. All rights reserved. 1. Introduction Antimicrobial peptides are small proteins with essential func- tions to the mammalian immune response, as well as many other organisms, participating primarily in innate immunity (Gallo et al., 2002; Nizet et al., 2001). Antimicrobial peptides have been impli- cated in a myriad of diseases, such as psoriasis, atopic dermatitis, sepsis, inflammatory bowel disease, infertility and cancer, being extensively studied for the development of new drugs (Pinheiro da Silva and Machado, 2012). Cationic host defense peptides are gene encoded and expressed in a variety of cell types, including monocyte/macrophages, neu- trophils, mast cells, keratinocytes and epithelial cells. LL-37 is constitutively expressed and inducible by microbial signa- ture molecules, inflammation and tissue injury (Mookherjee and Hancock, 2007). Myeloid cells express intracellular receptors that recognize viral and microbial nucleic acids and can be further activated by antimicrobial peptides (Latz et al., 2004; Diebold et al., 2004). LL- 37 also activates other membrane receptors, such as P2X7, an ATP-activated ion channel expressed by lymphocytes, dendritic cells, macrophages/microglia and non-hematopoietic cells, such as * Corresponding author. Tel.: +55 11 3061 8480. E-mail address: pinheirofabiano@hotmail.com (F. Pinheiro da Silva). fibroblasts, leading to massive calcium entry and can probably even induce ion fluxes in a receptor-independent manner (Tomasinsig et al., 2008). It has also been reported that LL-37 binds formyl peptide receptor-like 1 (FPRL1), inducing chemotaxis and angiogenesis (Kurosaka et al., 2005; Koczulla et al., 2003), and transactivates the epidermal growth factor receptor stimulating keratinocytes prolif- eration (Tokumaru et al., 2005; Schauber and Gallo, 2008). In the pulmonary epithelia, LL-37 induces nuclear translocation of NF- B and production of IL-6 (Pistolic et al., 2009) and in monocytes the activation of ERK and p38 (Bowdish et al., 2004). It has been reported, moreover, that self-DNA couples with LL-37 in autoim- mune diseases like psoriasis, triggering pathological interferon production after engulfment in endosomal compartments medi- ated by direct binding to Toll-like receptor 9 (Lande et al., 2007). LL-37, thus, can form a complex with DNA and induce modifications in its tridimensional structure caused by electrostatic fields. Due to its DNA-binding properties, we hypothesized that LL-37 should migrate to the nucleus during inflammation. Defensins, moreover, have been found inside the nucleus in prokaryotic cells, as described in the discussion section. 2. Methods Briefly, neutrophils from healthy individuals and septic patients were stained with anti-LL-37 antibody and DAPI and analyzed by 0040-8166/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tice.2013.04.003