The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
The Cathelicidin Anti-Microbial Peptide LL-37 is Involved in Re-Epithelialization of Human Skin Wounds and is Lacking in Chronic Ulcer Epithelium
Open accessAbstract
The human cathelicidin anti-microbial protein, hCAP18 is a component of the innate immune system and has broad anti-microbial activity conferred by its C-terminal fragment LL-37. hCAP18 is constitutively produced in leukocytes and is induced in barrier organs upon inflammation and infection. We demonstrate here a novel role for this peptide in re-epithelialization of skin wounds. We show that high levels of hCAP18 are produced in skin in vivo upon wounding. The highest hCAP18 levels are attained at 48 h post-injury, declining to pre-injury levels upon wound closure. hCAP18 is detected in the inflammatory infiltrate and in the epithelium migrating over the wound bed. In chronic ulcers, however, hCAP18 levels are low and immunoreactivity for hCAP18/LL-37 is absent in ulcer edge epithelium. Using a noninflammatory ex vivo wound healing model, composed of organ-cultured human skin, we show that hCAP18 is strongly expressed in healing skin epithelium, and that treatment with antibodies raised and affinity purified against LL-37, inhibits re-epithelialization in a concentration-dependent manner. Immunoreactivity for the proliferation marker Ki67 is absent in the epithelium of such inhibited wounds, suggesting that LL-37 may play a part in epithelial cell proliferation. Thus, we suggest that, in addition to being an anti-microbial peptide, LL-37 also plays a part in wound closure and that its reduction in chronic wounds impairs re-epithelialization and may contribute to their failure to heal.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Abnormal or dysfunctional AMP production has been associated with susceptibility to microbial infections and several other cutaneous diseases, including nonhealing wounds.29”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [29]
In the citing paper
“Wound fluids and skin wounds show elevated levels of cathelicidin expression in keratinocytes and other immune cells, reaching a maximum at 48 h.29”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [29]
In the citing paper
“Using a noninflammatory ex vivo wound healing model comprising organ-cultured human skin, it has been shown that hCAP18 is strongly expressed in healing skin epithelium and that treatment with affinity-purified antibodies raised against LL-37 inhibits reepithelialization in a concentration-dependent manner.29”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [29]
In the citing paper
“Cathelicidin is low in venous leg ulcers and absent at the margin of other nonhealing wounds.29”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [29]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302
Solid phase peptide synthesis utilizing 9‐fluorenylmethoxycarbonyl amino acids
Fields, G., & NOBLE, R. L. (1990) · International journal of peptide & protein research · doi:10.1111/j.1399-3011.1990.tb00939.x · Cited by 2,490
A peptide antibiotic from human skin
Harder, J., Bartels, J., Christophers, E., & Schröder, J. ‐. (1997) · Nature · doi:10.1038/43088 · Cited by 1,365
Yang, D., Chen, Q., Schmidt, A. P., Anderson, G. M., Wang, J., Wooters, J., Oppenheim, J. J., & Chertov, O. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.7.1069 · Cited by 1,238
Innate antimicrobial peptide protects the skin from invasive bacterial infection
Nizet, V., Ohtake, T., Lauth, X., Trowbridge, J., Rudisill, J., Dorschner, R. A., Pestonjamasp, V., Piraino, J., Huttner, K., & Gallo, R. L. (2001) · Nature · doi:10.1038/35106587 · Cited by 1,198
Human β-Defensin-1 Is a Salt-Sensitive Antibiotic in Lung That Is Inactivated in Cystic Fibrosis
Goldman, M. J., Anderson, G. M., Stolzenberg, E. D., Kari, U. P., ZASLOFF, M. A., & Wilson, J. M. (1997) · Cell · doi:10.1016/s0092-8674(00)81895-4 · Cited by 1,077
Defensins: Antimicrobial and Cytotoxic Peptides of Mammalian Cells
Lehrer, R. I., Lichtenstein, A. K., & Ganz, T. (1993) · Annual Review of Immunology · doi:10.1146/annurev.iy.11.040193.000541 · Cited by 1,000
Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors
Trengove, N. J., Stacey, M. C., Macauley, S., Bennett, N., Gibson, J., Burslem, F., Murphy, G., & Schultz, G. (1999) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1999.00442.x · Cited by 908
Sørensen, O. E., Follin, P., Johnsen, A. H., Calafat, J., Tjabringa, G. S., Hiemstra, P. S., & Borregaard, N. (2001) · Blood · doi:10.1182/blood.v97.12.3951 · Cited by 894
Self-citationFrohm, M., Agerberth, B., Ahangari, G., Ståhle‐Bäckdahl, M., Lidén, S., Wigzell, H., & Gudmundsson, G. H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.24.15258 · Cited by 803
Self-citationAgerberth, B., Charo, J., Werr, J., Olsson, B., Idali, F., Lindbom, L., Kiessling, R., Jörnvall, H., Wigzell, H., & Gudmundsson, G. H. (2000) · Blood · doi:10.1182/blood.v96.9.3086 · Cited by 758
Bals, R., Wang, X., ZASLOFF, M. A., & Wilson, J. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9541 · Cited by 745
Antimicrobial peptides in mammalian and insect host defence
Lehrer, R. I., & Ganz, T. (1999) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)80005-3 · Cited by 734
Conformation-dependent Antibacterial Activity of the Naturally Occurring Human Peptide LL-37
Johansson, J., Gudmundsson, G. H., Rottenberg, M. E., Berndt, K. D., & Agerberth, B. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.6.3718 · Cited by 662
Gudmundsson, G. H., Agerberth, B., Odeberg, J., Bergman, T., Olsson, B., & Salcedo, R. (1996) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1996.0325z.x · Cited by 579
Dorschner, R. A., Pestonjamasp, V. K., Tamakuwala, S., Ohtake, T., Rudisill, J., Nizet, V., Agerberth, B., Gudmundsson, G. H., & Gallo, R. L. (2001) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2001.01340.x · Cited by 567
Agerberth, B., Gunne, H., Odeberg, J., Kogner, P., Boman, H. G., & Gudmundsson, G. H. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.1.195 · Cited by 502
Growth factors and wound healing: Part II. Role in normal and chronic wound healing
Bennett, N. T., & Schultz, G. S. (1993) · The American Journal of Surgery · doi:10.1016/s0002-9610(05)80589-6 · Cited by 455
Islam, D., Bandholtz, L., Nilsson, J., Wigzell, H., Christensson, B., Agerberth, B., & Gudmundsson, G. H. (2001) · Nature Medicine · doi:10.1038/84627 · Cited by 429
Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4
Echtermeyer, F. G., Streit, M., Wilcox‐Adelman, S. A., Saoncella, S., Denhez, F., Detmar, M. J., & Goetinck, P. F. (2001) · Journal of Clinical Investigation · doi:10.1172/jci10559 · Cited by 427
PR39, a peptide regulator of angiogenesis
Li, J., Post, M. J., Volk, R., Gao, Y., Li, M., Métais, C., Sato, K., Tsai, J. C., Aird, W. C., ROSENBERG, R. D., et al. (2000) · Nature Medicine · doi:10.1038/71527 · Cited by 384
Sørensen, O. E., Arnljots, K., Cowland, J. B., Bainton, D. F., & Borregaard, N. (1997) · Blood · doi:10.1182/blood.v90.7.2796 · Cited by 368
Self-citationGallo, R. L., Ono, M., Povsic, T. J., Page, C., Eriksson, E. K., Klagsbrun, M., & Bernfield, M. R. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.11035 · Cited by 361
hCAP‐18, a cathelin/pro‐bactenecin‐like protein of human neutrophil specific granules
Cowland, J. B., Johnsen, A. H., & Borregaard, N. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00634-l · Cited by 354
Self-citationNilsson, M. F., Sandstedt, B., Sørensen, O. E., Weber, G., Borregaard, N., & Ståhle‐Bäckdahl, M. (1999) · Infection and Immunity · doi:10.1128/iai.67.5.2561-2566.1999 · Cited by 351
Self-citationAntimicrobial Peptides as Mediators of Epithelial Host Defense
Huttner, K. M., & Bevins, C. L. (1999) · Pediatric Research · doi:10.1203/00006450-199906000-00001 · Cited by 280
Inhibition of cell proliferation by chronic wound fluid
BUCALO, B. D., Eaglstein, W. H., & Falanga, V. (1993) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1993.10308.x · Cited by 262
Nagaoka, I., Hirota, S., Niyonsaba, F., Hirata, M., Adachi, Y., Tamura, H., & Heumann, D. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.6.3329 · Cited by 258
Herrick, S. E., Sloan, P., McGurk, M., Freak, L., McCollum, C. N., & Ferguson, M. W. J. (1992) · PubMed Central · Cited by 246
Malm, J., Sørensen, O. E., Persson, T., Frohm‐Nilsson, M., Johansson, B., Bjartell, A. S., Lilja, H. G., Ståhle‐Bäckdahl, M., Borregaard, N., & Egesten, A. (2000) · Infection and Immunity · doi:10.1128/iai.68.7.4297-4302.2000 · Cited by 223
Self-citationBiochemical and Antibacterial Analysis of Human Wound and Blister Fluid
Frohm, M., Gunne, H., Bergman, A., Agerberth, B., Bergman, T., Boman, A., Lidén, S., Jörnvall, H., & Boman, H. G. (1996) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1996.0086n.x · Cited by 212
An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma
Sørensen, O. E., Cowland, J. B., Askaa, J., & Borregaard, N. (1997) · Journal of Immunological Methods · doi:10.1016/s0022-1759(97)00084-7 · Cited by 209
Self-citationPrimary structures of MCP-1 and MCP-2, natural peptide antibiotics of rabbit lung macrophages.
Selsted, M. E., Brown, D. M., DeLange, R. J., & Lehrer, R. I. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43888-9 · Cited by 205
Antibiotic peptides from higher eukaryotes: biology and applications
Ganz, T., & Lehrer, R. I. (1999) · Molecular Medicine Today · doi:10.1016/s1357-4310(99)01490-2 · Cited by 197
Schmidtchen, A., Frick, I.-M., & Björck, L. (2001) · Molecular Microbiology · doi:10.1046/j.1365-2958.2001.02251.x · Cited by 160
Primary structure of a new cysteine proteinase inhibitor from pig leucocytes
Ritonja, A., Kopitar, M., Jerala, R., & Türk, V. (1989) · FEBS Letters · doi:10.1016/0014-5793(89)81093-2 · Cited by 148
Inoue, M., Kratz, G., Hægerstrand, A., & Ståhle‐Bäckdahl, M. (1995) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12605917 · Cited by 137
Self-citationGrowth Factors and Chronic Wounds: The Need to Understand the Microenvironment
Falanga, V. (1992) · The Journal of Dermatology · doi:10.1111/j.1346-8138.1992.tb03756.x · Cited by 126
Structural, functional analysis and localization of the human CAP18 gene
Larrick, J. W., Lee, J., Ma, S.-W., Li, X., Francke, U., Wright, S. C., & Balint, R. F. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01199-4 · Cited by 76
Effect of chronic wound fluid on fibroblasts
Phillips, T. J., Al-Amoudi, H. O., Leverkus, M., & Park, H.-Y. (1998) · Journal of Wound Care · doi:10.12968/jowc.1998.7.10.527 · Cited by 69
Expression of 92-kDa Type IV Collagenase mRNA by Eosinophils Associated with Basal Cell Carcinoma
Ståhle‐Bäckdahl, M., Sudbeck, B. D., Eisen, A. Z., Welgus, H. G., & Parks, W. C. (1992) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12616171 · Cited by 66
Self-citationKratz, G., Lake, M., & Gidlund, M. (1994) · Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery · doi:10.3109/02844319409071187 · Cited by 58
Self-citationA microscopical study of wound repair in the human placenta
Watson, A. L., & Burton, G. J. (1998) · Microscopy Research and Technique · doi:10.1002/(sici)1097-0029(19980901)42:5 · Cited by 20
Self-citationPhillips, T. J., Palko, M. J., & Bhawan, J. (1994) · Journal of the American Academy of Dermatology · doi:10.1016/s0190-9622(94)70009-5 · Cited by 16
Cited by
Sorted by citations
Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide
Lande, R., Gregorio, J., Facchinetti, V., Chatterjee, B., Wang, Y.-H., Homey, B., Cao, W., Wang, Y.-H., Su, B., Nestle, F. O., et al. (2007) · Nature · doi:10.1038/nature06116 · Cited by 1,910
Cutting Edge: 1,25-Dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression
Wang, T. T., Nestel, F. P., Bourdeau, V., Nagai, Y., Wang, Q., Liao, J. L., Tavera-Mendoza, L. E., Lin, R., Hanrahan, J. W., Mader, S., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.5.2909 · Cited by 1,661
Epithelialization in Wound Healing: A Comprehensive Review
Pastar, I., Stojadinović, O., Yin, N. C., Ramirez, H. A., Nusbaum, A. G., Sawaya, A. P., Patel, S. B., Khalid, L., Isseroff, R. R., & Tomic‐Canic, M. (2014) · Advances in Wound Care · doi:10.1089/wound.2013.0473 · Cited by 1,604
Antimicrobial host defence peptides: functions and clinical potential
Mookherjee, N., Anderson, M. A., Haagsman, H. P., & Davidson, D. J. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0058-8 · Cited by 1,502
AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense
Lai, Y., & Gallo, R. L. (2009) · Trends in Immunology · doi:10.1016/j.it.2008.12.003 · Cited by 1,322
Metadata
- Authors
- Heilborn, J. D., Nilsson, M. F., Sørensen, O., Ståhle-Bäckdahl, M., Kratz, G., Weber, G., & Borregaard, N.
- Affiliations
- Karolinska Institutet (SE)
- Rigshospitalet (DK)
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 120
- Issue
- 3
- Pages
- 379-389
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2072432297
- Cited by
- 572
- References
- 44
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 15 · 2023: 22 · 2022: 19 · 2021: 28 · 2020: 17 · 2019: 15 · 2018: 21 · 2017: 28 · 2016: 28 · 2015: 25 · 2014: 25 · 2013: 33 · 2012: 39
- FWCI
- 24.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Keywords
- LL-37, cathelicidin, hCAP18, re-epithelialization, skin wound healing, chronic wounds, chronic ulcers, epithelial cell proliferation, Ki-67, innate immunity, antimicrobial peptides, antibody inhibition
- MeSH terms
- Antibodies, Bacillus megaterium, Chronic Disease, Dose-Response Relationship, Drug, Epithelium, Humans, Immune Sera, Leg Ulcer, Organ Culture Techniques, Skin, Wound Healing, Wounds, Penetrating, Keratinocytes, Ki-67 Antigen, Antimicrobial Cationic Peptides, Cathelicidins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
