Sequence determinants in the cathelicidin LL-37 that promote inflammation via presentation of RNA to scavenger receptors

Abstract

Cathelicidins such as the human 37-amino acid peptide (LL-37) are peptides that not only potently kill microbes but also trigger inflammation by enabling immune recognition of endogenous nucleic acids. Here, a detailed structure–function analysis of LL-37 was performed to understand the details of this process. Alanine scanning of 34-amino acid peptide (LL-34) showed that some variants displayed increased antimicrobial activity against Staphylococcus aureus and group A Streptococcus. In contrast, different substitutions clustered on the hydrophobic face of the LL-34 alpha helix inhibited the ability of those variants to promote type 1 interferon expression in response to U1 RNA or to present U1 to the scavenger receptor (SR) B1 on the keratinocyte cell surface. Small-angle X-ray scattering experiments of the LL-34 variants LL-34, F5A, I24A, and L31A demonstrated that these peptides form cognate supramolecular structures with U1 characterized by inter-dsRNA spacings of approximately 3.5 nm, a range that has been previously shown to activate toll-like receptor 3 by the parent peptide LL-37. Therefore, while alanine substitutions on the hydrophobic face of LL-34 led to loss of binding to SRs and the complete loss of autoinflammatory responses in epithelial and endothelial cells, they did not inhibit the ability to organize with U1 RNA in solution to associate with toll-like receptor 3. These observations advance our understanding of how cathelicidin mediates the process of innate immune self-recognition to enable inert nucleic acids to trigger inflammation. We introduce the term “innate immune vetting” to describe the capacity of peptides such as LL-37 to enable certain nucleic acids to become an inflammatory stimulus through SR binding prior to cell internalization. Cathelicidins such as the human 37-amino acid peptide (LL-37) are peptides that not only potently kill microbes but also trigger inflammation by enabling immune recognition of endogenous nucleic acids. Here, a detailed structure–function analysis of LL-37 was performed to understand the details of this process. Alanine scanning of 34-amino acid peptide (LL-34) showed that some variants displayed increased antimicrobial activity against Staphylococcus aureus and group A Streptococcus. In contrast, different substitutions clustered on the hydrophobic face of the LL-34 alpha helix inhibited the ability of those variants to promote type 1 interferon expression in response to U1 RNA or to present U1 to the scavenger receptor (SR) B1 on the keratinocyte cell surface. Small-angle X-ray scattering experiments of the LL-34 variants LL-34, F5A, I24A, and L31A demonstrated that these peptides form cognate supramolecular structures with U1 characterized by inter-dsRNA spacings of approximately 3.5 nm, a range that has been previously shown to activate toll-like receptor 3 by the parent peptide LL-37. Therefore, while alanine substitutions on the hydrophobic face of LL-34 led to loss of binding to SRs and the complete loss of autoinflammatory responses in epithelial and endothelial cells, they did not inhibit the ability to organize with U1 RNA in solution to associate with toll-like receptor 3. These observations advance our understanding of how cathelicidin mediates the process of innate immune self-recognition to enable inert nucleic acids to trigger inflammation. We introduce the term “innate immune vetting” to describe the capacity of peptides such as LL-37 to enable certain nucleic acids to become an inflammatory stimulus through SR binding prior to cell internalization. Cathelicidins are a family of antimicrobial and immunomodulatory peptides found across diverse species and produced by many cell types (1Zasloff M. Antimicrobial peptides of multicellular organisms.Nature. 2002; 415: 389-395Crossref PubMed Scopus (6393) Google Scholar). In humans, only a single cathelicidin gene called CAMP is known, and it encodes a mature 37-amino acid peptide (LL-37) that is cationic, alpha helical, and amphipathic. LL-37 has multiple biological actions in addition to its capacity to kill bacteria. These include chemotaxis, wound healing, lipopolysaccharide neutralization, and angiogenesis (2Salvado M.D. Di Gennaro A. Lindbom L. Agerberth B. Haeggström J.Z. Cathelicidin LL-37 induces angiogenesis via PGE2-EP3 signaling in endothelial cells, in vivo inhibition by aspirin.Arterioscler. Thromb. Vasc. Biol. 2013; 33: 1965-1972Crossref PubMed Scopus (39) Google Scholar, 3Dürr U.H.N. Sudheendra U.S. Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides.Biochim. Biophys. Acta Biomembr. 2006; 1758: 1408-1425Crossref PubMed Scopus (683) Google Scholar). Cathelicidin is an important component in neutrophil extracellular traps that promote innate and adaptive immune responses (4Herster F. Bittner Z. Archer N.K. Dickhöfer S. Eisel D. Eigenbrod T. Knorpp T. Schneiderhan-Marra N. Löffler M.W. Kalbacher H. Vierbuchen T. Heine H. Miller L.S. Hartl D. Freund L. et al.Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis.Nat. Commun. 2020; 11: 1-13Crossref PubMed Scopus (53) Google Scholar). The active LL-37 peptide is processed from proprotein hCAP18 by protease-mediated cleavage with neutrophil proteinase 3 and epithelial kallikreins like kallikrein gene 5 (5Yamasaki K. Di Nardo A. Bardan A. Murakami M. Ohtake T. Coda A. Dorschner R.A. Bonnart C. Descargues P. Hovnanian A. Morhenn V.B. Gallo R.L. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Nat. Med. 2007; 13: 975-980Crossref PubMed Scopus (573) Google Scholar, 6Sørensen O.E. Follin P. Johnsen A.H. Calafat J. Sandra Tjabringa G. Hiemstra P.S. Borregaard N. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3.Blood. 2001; 97: 3951-3959Crossref PubMed Scopus (674) Google Scholar). Previous studies have shown that human autoinflammatory diseases like rosacea or psoriasis are promoted by the presence of excess LL-37 within the skin (5Yamasaki K. Di Nardo A. Bardan A. Murakami M. Ohtake T. Coda A. Dorschner R.A. Bonnart C. Descargues P. Hovnanian A. Morhenn V.B. Gallo R.L. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Nat. Med. 2007; 13: 975-980Crossref PubMed Scopus (573) Google Scholar). Inflammation present in human diseases such as psoriasis and rosacea is amplified in part through the capacity of LL-37 to enhance the recognition of self nucleic acids. One example is noncoding U1 dsRNA that is released from damaged cells, leading to activation of endosomal or cytosolic pattern recognition receptors with subsequent release of inflammatory cytokines like tumor necrosis factor alpha or type 1 interferons (7Kulkarni N.N. Takahashi T. Sanford J.A. Tong Y. Gombart A.F. Hinds B. Cheng J.Y. Gallo R.L. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression.J. Invest. Dermatol. 2020; 140: 645-655.e6Abstract Full Full PubMed Scopus Google Scholar, C. T. B. J. L. Gallo R.L. self noncoding RNA and is by Med. PubMed Scopus Google Scholar, A. K. Y. C. Sanford J.A. N. M. Y. J. T. et peptide LL37 and signaling by skin Full Full PubMed Google Scholar). LL-37 expression has also been in the of diseases like and (5Yamasaki K. Di Nardo A. Bardan A. Murakami M. Ohtake T. Coda A. Dorschner R.A. Bonnart C. Descargues P. Hovnanian A. Morhenn V.B. Gallo R.L. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Nat. Med. 2007; 13: 975-980Crossref PubMed Scopus (573) Google Scholar, Ohtake T. C. M. T. Gallo R.L. antimicrobial peptides and skin in J. Med. 2002; PubMed Scopus Google Scholar, K. Agerberth B. K. of the antimicrobial peptide LL-37 in human Thromb. Vasc. Biol. 2006; PubMed Scopus Google Scholar, K. M. T. K. S. The of cathelicidin LL-37 in PubMed Scopus Google that the autoinflammatory activity of LL-37 important to a range of human acid and the alpha helix are antimicrobial activity of LL-37 G. B. Y. F. C. D. T. of antimicrobial with human cathelicidin in and and of peptides from LL-37 has been to enhance antimicrobial against and and with or its inflammatory antimicrobial T. A. M. Antimicrobial and lipopolysaccharide neutralization, and inhibition by of of human cathelicidin PubMed Scopus Google Scholar, L. J. LL37 via binding to the and PubMed Scopus Google Scholar, B. K. Gallo R.L. activity of and in skin Invest. Dermatol. Full Full PubMed Scopus Google Scholar, Y. G. K. Y. J. K. human cathelicidin antimicrobial peptides inhibit 2020; Full Full PubMed Scopus Google Scholar, R.L. Dorschner M.D. C. A. Di Nardo A. antimicrobial from human cathelicidin of PubMed Scopus Google Scholar, C. B. K. M. P.S. of peptides from the human antimicrobial peptide LL-37 active against by a of PubMed Scopus Google Scholar, S. T. and of peptides enhance antimicrobial activity and 2020; 11: PubMed Scopus Google Scholar, A. H. Hiemstra P.S. A. peptides Staphylococcus aureus from human skin PubMed Scopus Google Scholar, of antimicrobial peptides from human cathelicidin LL-37 on 2013; PubMed Scopus Google Scholar). is how LL-37 promotes through its inflammatory LL-37 has been shown to its and by but its immunomodulatory are and on its capacity to trigger activation of pattern recognition and cell receptors like toll-like receptor factor and peptide receptor M. Cathelicidins and 2020; 11: PubMed Scopus Google Scholar, peptide signaling in to cell activation in PubMed Scopus Google Scholar, J. O.E. Borregaard N. Hiemstra P.S. The antimicrobial peptide LL-37 innate the epithelial by of the factor PubMed Google Scholar, D. S. M. M. Gennaro A. The human cathelicidin LL-37 a peptide and Biophys. Acta Biomembr. PubMed Scopus Google Scholar). LL-37 has also been shown to as an by and responses J. N. J. S. and LL37 are in active psoriasis and with and Dermatol. PubMed Scopus Google Scholar, C. D. G. C. G. L. B. S. L. P. P. et antimicrobial peptide LL37 is a in psoriasis.Nat. Commun. PubMed Scopus Google Scholar, L. S. B. L. A. L. L. F. M. A. et are present in in PubMed Scopus Google Scholar). receptor activation by LL-37 has been these have not binding to receptor or a of this important In the present a alanine of a of LL-37 to acid are to it to enable immune recognition self nucleic acids such as U1 We to this process as “innate immune vetting” as the presence of LL-37 in a or cell nucleic acid to become a previously this and understanding of how LL-37 inflammation. A peptide with a of acids the of LL-37 as LL-34 its activity against group A and its ability to promote an inflammatory response in response to U1 dsRNA T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). LL-34 was the of LL-37 that antimicrobial and immune a of peptides with substitutions of alanine acid of the LL-34 parent peptide We the the LL-34 parent peptide and the alanine and against Staphylococcus aureus LL-34 peptides of to with bacteria. The was was of I24A, and S. aureus potently as with the LL-34 parent peptide that an of and a with the parent of these in the against S. aureus the the of the peptides in human by release The LL-34 parent peptide in release by was 5 with LL-34 parent and by the and a of peptides a of was a of on these experiments LL-34 peptides to of parent peptide and its alanine are in peptide is in a The peptide is We that of acid in LL-34 peptide with a acid alanine the acid its ability to inflammation in response to U1 and human endothelial with LL-34 parent peptide and of the and the of in the by A and with peptides did not release of in or We and with a of U1 dsRNA and the LL-34 peptides and with U1 dsRNA and of the LL-34 I24A, and of as with with a of U1 dsRNA and LL-34 parent peptide A pattern of release was with the peptide and U1 dsRNA of the acids that with alanine leading to this loss of on a in showed that substitutions on the hydrophobic in this loss and the of the showed that on the hydrophobic the ability of LL-34 peptides to U1 dsRNA We by to gene expression type 1 interferon and cytokines and in with LL-34 I24A, and or in with U1 dsRNA with peptides F5A, I24A, and L31A increased gene expression of the expression of and was not with U1 dsRNA showed a in gene expression of and with F5A, I24A, and of antimicrobial of these peptides on the of S. aureus and and showed that peptides that the capacity to responses such as F5A, I24A, and L31A increased capacity to inhibit of of the with against LL-34 and demonstrated antimicrobial activity but loss of inflammatory activity with U1 analysis with a on these peptide to understanding of the inflammation. in the with a single of of U1 dsRNA LL-34 I24A, or of the are shown in We gene expression of and in these The gene expression of and was in with U1 dsRNA and and L31A with with U1 dsRNA and LL-34 was in with the in We also the of immune to the skin with A in cells, and was in with U1 dsRNA and LL-34 parent peptide with U1 dsRNA and increased in the a in cell was in with U1 dsRNA and L31A with U1 dsRNA and or U1 dsRNA and L31A showed a in and neutrophil with with LL-34 parent peptide and U1 that the a loss of innate activity in vivo and these in in cell that LL-34 and L31A have capacity to promote inflammation. was to a and immune in to U1 LL-34 I24A, and a of U1 dsRNA and LL-34 I24A, or the of showed in with U1 and LL-34 and U1 and U1 L31A A and and A and analysis showed of that not in with U1 dsRNA and with U1 dsRNA and LL-34 parent peptide These type 1 interferon response to and signaling of from with U1 and in to U1 and LL-34 parent showed that type interferon signaling and and gene and We the of signaling with with U1 LL-34 I24A, or with a of U1 and LL-34 U1 and I24A, or U1 and L31A of 1 and interferon factor was in with U1 and in to U1 and LL-34 parent peptide the that showed substitutions with alanine and the loss of and innate immune signaling in to U1 dsRNA and prior in and in vivo observations on In have shown that the of U1 RNA and LL-37 is by cell scavenger receptors prior to internalization. via the the U1 is by the or the endosomal pattern recognition receptors to and signaling (7Kulkarni N.N. Takahashi T. Sanford J.A. Tong Y. Gombart A.F. Hinds B. Cheng J.Y. Gallo R.L. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression.J. Invest. Dermatol. 2020; 140: 645-655.e6Abstract Full Full PubMed Scopus Google Scholar, T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). SRs are to the activity of the parent LL-34 with against SR and of SRs was with A was as a with U1 dsRNA and LL-34 parent peptide in SR A and A of multiple SRs showed expression of or with U1 and LL-34 parent A and is in with that that multiple SRs form a with U1 dsRNA and LL-37 peptide T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). responses to LL-34 showed the on the expression of the SR in and peptides of a with U1 The binding of peptide to or U1 to was by of by showed that the presence of LL-34 parent LL-34 to with and L31A did not and binding of U1 dsRNA to was with parent LL-34 but not with or L31A and We also the of binding of U1 dsRNA on the of in the presence of LL-34 to U1 and LL-34 parent LL-34 I24A, LL-34 LL-34 and LL-34 on to binding of U1 to in the presence of peptides LL-34 parent peptide and LL-34 binding of U1 on the cell with LL-34 and LL-34 with an LL-34 that showed binding of U1 dsRNA on The addition of excess U1 dsRNA in the presence of U1 RNA and LL-34 parent peptide inhibited the binding of U1 dsRNA to with and to a of to the binding and L31A These observations that while some with the cell U1 binding is on LL-34 and by acid substitutions to those that inhibit capacity to promote inflammation or U1 to that LL-34 acid substitutions in the of peptides to promote inflammation by immune of dsRNA also in an to enable binding of U1 RNA to SRs and subsequent binding to the cell surface. The structures of U1 peptide by X-ray scattering to with prior of U1 with LL-34 parent peptide and LL-34 F5A, LL-34 I24A, and LL-34 with U1 dsRNA to form an the LL-34 parent peptide and U1 dsRNA pattern is with the of a supramolecular with an dsRNA an of as the in of the LL-34 the was was also in U1 with LL-34 a inter-dsRNA of with in this range to activate the was not by the alanine the LL-34 and LL-34 L31A increased with LL-34 parent the of these dsRNA structures that in the immune activation is the and that immune of these the cell a A of the by in acid by or substitutions has the the antimicrobial and inflammatory response of cathelicidin G. B. Y. F. C. D. T. of antimicrobial with human cathelicidin in and Scholar). In this the of of LL-34 peptide with alanine on the and In our prior of LL-37 peptide and showed that a 34-amino acid peptide LL-34 from LL-37 the and immunomodulatory capacity T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). by of with showed that the LL-34 peptide its antimicrobial activity against it the capacity to U1 dsRNA released from cells, and to an inflammatory response in the previously that the antimicrobial activity of cathelicidin from its ability to U1 this of innate immune of damaged RNA by cathelicidin, a of alanine Alanine scanning was single substitutions with alanine not or in the peptide and also not the like the or substitutions J.A. of by PubMed Google Scholar, F. scanning A and to and PubMed Scopus Google Scholar). of and human endothelial by the showed in the and in the of the was it has been previously shown that alanine and substitutions in peptide enhance or inhibit its response S. T. Alanine and of the peptide antimicrobial PubMed Scopus Google the activity of the against S. aureus and that LL-34 I24A, and antimicrobial activity We the ability of the to U1 dsRNA and L31A showed with the parent LL-34 peptide the in with U1 a loss of ability to U1 The and L31A active as increased gene expression of was We previously shown that with U1 dsRNA and LL-37 a inflammatory response in in the (7Kulkarni N.N. Takahashi T. Sanford J.A. Tong Y. Gombart A.F. Hinds B. Cheng J.Y. Gallo R.L. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression.J. Invest. Dermatol. 2020; 140: 645-655.e6Abstract Full Full PubMed Scopus Google Scholar). We a response in with a of U1 dsRNA and LL-34 with and expression and increased of immune to the of or L31A and U1 dsRNA showed a immune response a loss of recognition of RNA of the alanine a understanding of the by the alanine a of with LL-34 parent I24A, L31A in with U1 analysis showed that with peptides in with U1 dsRNA in of to type 1 interferon signaling and inflammatory response In and rosacea the signaling is recognition of the self nucleic acids by cathelicidin, to activation of a type 1 interferon response and adaptive to cell activation (7Kulkarni N.N. Takahashi T. Sanford J.A. Tong Y. Gombart A.F. Hinds B. Cheng J.Y. Gallo R.L. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression.J. Invest. Dermatol. 2020; 140: 645-655.e6Abstract Full Full PubMed Scopus Google Scholar, A. K. Y. C. Sanford J.A. N. M. Y. J. T. et peptide LL37 and signaling by skin Full Full PubMed Google Scholar). showed that the and a loss of the signaling by the of and The RNA has been shown to activate a type 1 interferon response by cell SRs and the inflammatory response by of the to the or and activation of or pattern recognition receptors A. J. receptor 3 response in human epithelial 2006; PubMed Scopus Google Scholar, S. D. P. A. A. different dsRNA leading to or response in Biol. Full Full PubMed Scopus Google Scholar, A. J. receptor promotes activation in human PubMed Scopus Google Scholar). important in our is that self RNA U1 is inert and not by the by LL-37 A. K. Y. C. Sanford J.A. N. M. Y. J. T. et peptide LL37 and signaling by skin Full Full PubMed Google Scholar, T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). The of U1 to LL-37 in the of multiple SRs on the cell leading to via The of by LL-37 like has been also In associate with from damaged and activate via toll-like receptor an inflammatory response in B. S. as a to an response via and PubMed Scopus Google Scholar). A also showed that a type 1 is released from skin and nucleic acids to a inflammatory response to wound by the of like factor J. C. P. A. T. C. B. S. B. M. The skin type innate responses in 2020; PubMed Scopus Google Scholar). the of innate immune by like LL-37 and as a and immune response on the of by The of nucleic peptide is on SRs a of pattern recognition receptors that and or like like and the immune responses in diseases like and J. D. S. receptors in and 2013; 13: PubMed Scopus Google Scholar, L. S. S. receptors in innate 2002; PubMed Scopus Google Scholar). SRs that are J. D. S. receptors in and 2013; 13: PubMed Scopus Google Scholar). showed that SRs are different SRs are to form with U1 dsRNA and LL-37 peptide and have that via T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). In this the of SRs in the expression of and in with a of U1 dsRNA and LL-34 parent peptide that the of U1 with SR is LL-34 is and L31A leading to a loss of response 1 and The the binding and LL-34 peptides and U1 the U1 ability is not and the structures of dsRNA are not by the alanine and LL-34 parent peptide and these the of U1 dsRNA is to to Previous showed that inter-dsRNA spacings to range has the activation with Takahashi T. T. J. Gallo R.L. of peptide toll-like receptor 11: PubMed Scopus Google Scholar). that the of peptide and nucleic acid to by SR and a in recognition was in the and L31A that the to present to studies are to how the and L31A of the and to pattern recognition receptors like and the of these capacity of the peptides to or and capacity of in addition to U1 RNA to the binding of a A showed that nucleic acid are by the by of A SRs and via by M. A. C. A scavenger receptor are and promote nucleic acid Invest. Dermatol. Full Full PubMed Scopus Google Scholar). In our that the hydrophobic face of the cathelicidin peptide is its ability to dsRNA and an immune The details of how the of cathelicidin to the inflammatory activity the of that as of cathelicidin, inflammation and and to in a LL-37 and LL-34 Alanine to the The LL-34 alanine peptides and was performed by the the peptides and U1 dsRNA and its form as previously T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). U1 dsRNA is a as previously C. T. B. J. L. Gallo R.L. self noncoding RNA and is by Med. PubMed Scopus Google Scholar, T. Gallo R.L. receptor 3 activation is skin Invest. Dermatol. Full Full PubMed Scopus Google Scholar). to the the U1 RNA was and to by the of and with U1 dsRNA LL-34 peptides as previously (7Kulkarni N.N. Takahashi T. Sanford J.A. Tong Y. Gombart A.F. Hinds B. Cheng J.Y. Gallo R.L. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression.J. Invest. Dermatol. 2020; 140: 645-655.e6Abstract Full Full PubMed Scopus Google Scholar). A of was in the part of the the with and and in complete on and processed gene expression and within 1 in complete on and within with and and through a to cell with with by with immune The immune and cell expression of immune cell performed by the and by from the was was performed with and on a with S. aureus and S. aureus in with was in with was in with a with cell a of and with or to of the and to by an and The was to a of 1 in The LL-34 parent and alanine the A of the was the that of with or the LL-34 peptide and to with of was by the of a The of was by the peptide that inhibited was performed to from RNA was a RNA RNA was to the performed on a with a was on with analysis was performed on The was in the K. C. A. of innate and and 2013; PubMed Scopus Google Scholar). RNA from RNA was on the of RNA was to with gene expression to as previously A. K. Y. C. Sanford J.A. N. M. Y. J. T. et peptide LL37 and signaling by skin Full Full PubMed Google Scholar, N.N. F. Sanford J.A. C. Gallo R.L. and an innate immune response to Invest. Dermatol. Full Full PubMed Scopus Google Scholar). experiments performed on a to was the of gene expression and the 2001; PubMed Scopus Google Scholar). in complete with protease and The was and was was in complete was with of was a to to a and with The from extracellular and extracellular and The on an was performed as previously T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar, N.N. F. Sanford J.A. C. Gallo R.L. and an innate immune response to Invest. Dermatol. Full Full PubMed Scopus Google Scholar). skin was in and in the the and of the also from the on with was performed as previously T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). in to and with LL-34 peptides by with U1 dsRNA 1 U1 dsRNA and LL-34 peptides with in in in a and with in and LL-34 LL-37 was with the with and to and in a and of the was performed to the on with and by of with The was and the are of a single against SRs from was performed as previously T. N.N. Gallo R.L. Cathelicidin promotes inflammation by enabling binding of to cell scavenger PubMed Scopus Google Scholar). of by and U1 dsRNA and and experiments the and the and was a of The the J. Scopus Google Scholar). multiple different to the present in the scattering was The the The inter-dsRNA is from the by the We also of We the factor as is the of the and is the F. T. C. L. D. J. M. of antimicrobial PubMed Scopus Google Scholar). The and the was in The pattern but the as is only single in a with of has a the C. Di J. F. M. N. M. P. antimicrobial peptides that present to Commun. 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