Complement deficiency promotes cutaneous wound healing in mice
Open accessAbstract
Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3−/− mice exhibit accelerated early stages of wound healing. Reconstitution of C3−/− mice with serum from C3+/+ mice or purified human C3 abrogated the accelerated wound-healing phenotype. Wound histology of C3−/− mice revealed a reduction in inflammatory infiltrate compared with C3+/+ mice. C3 deficiency also resulted in increased accumulation of mast cells and advanced angiogenesis. We further show that mice deficient in the downstream complement effector C5 exhibit a similar wound-healing phenotype, which is recapitulated in C5aR1−/− mice, but not C3aR−/− or C5aR2−/− mice. Taken together, these data suggest that C5a signaling through C5aR may in part play a pivotal role in recruitment and activation of inflammatory cells to the wound environment, which in turn could delay the early stages of cutaneous wound healing. These findings also suggest a previously underappreciated role for complement in wound healing, and may have therapeutic implications for conditions of delayed wound healing.
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C3 functions as a negative regulator of tissue healing, since C3-deficient mice exhibit increased wound healing and angiogenesis.
“Specifically, C3 functions as a negative regulator of tissue healing, since C3-deficient mice exhibit an increased wound healing and angiogenesis [76].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [76]
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Cites
Singer, A. J., & Clark, R. A. F. (1999) · New England Journal of Medicine · doi:10.1056/nejm199909023411006 · Cited by 6,106 · see citing works
Wound Healing--Aiming for Perfect Skin Regeneration
Martin, P. B. (1997) · Science · doi:10.1126/science.276.5309.75 · Cited by 4,814 · cited 1× · see citing works
“overlapping stages, as follows: hemostasis, inflammation, tissue proliferation, and wound resolution and remodeling (1, 2).”
BackgroundPathophysiology of acute wound healing
Li, J., Chen, J., & Kirsner, R. S. (2007) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2006.09.007 · Cited by 3,997 · see citing works
Complement: a key system for immune surveillance and homeostasis
Ricklin, D., Hajishengallis, G., Yang, K., & Lambris, J. D. (2010) · Nature Immunology · doi:10.1038/ni.1923 · Cited by 3,654 · cited 3× · see citing works
“The complement system is composed of several plasma proteins, including pattern-recognition molecules, enzymes and enzymatic complexes, regulators, and receptors, interacting with numerous immune mediators (5).”
BackgroundInfluentialSelf-citationGeneration of C5a in the absence of C3: a new complement activation pathway
Huber-Lang, M. S., Sarma, J. V., Zetoune, F. S., Rittirsch, D., Neff, T. A., McGuire, S. R., Lambris, J. D., Warner, R. L., Flierl, M. A., Hoesel, L. M., et al. (2006) · Nature Medicine · doi:10.1038/nm1419 · Cited by 976 · cited 2× · see citing works
“Indeed, C3 mice have been shown to contain significantly higher levels of thrombin (6), which by itself can assist in the initial stages of healing through direct cleavage of C5, thereby leading to the attraction of immune cells at the very early stages of the healing process.”
BackgroundSelf-citationBickers (2006) · doi:10.1016/j.jaad.2006.05.048 · Cited by 741 · see citing works
A Role for Skin γδ T Cells in Wound Repair
Jameson, J., Ugarte, K., Chen, N., Yachi, P. P., Fuchs, E. V., Boismenu, R., & Havran, W. L. (2002) · Science · doi:10.1126/science.1069639 · Cited by 639 · see citing works
Accelerated wound closure in neutrophil-depleted mice
Dovi, J. V., He, L.-K., & DiPietro, L. A. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0802406 · Cited by 525 · see citing works
Ritis, K., Doumas, M. N., Mastellos, D. C., Micheli, A., Giaglis, S., Magotti, P., Rafail, S., Kartalis, G., Sideras, P., & Lambris, J. D. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.7.4794 · Cited by 492 · cited 2× · see citing works
“Apart from the role of complement on immune cells, recent work has also shown the involvement of complement in other key processes playing roles in wound healing, such as fibroblast migration and activation (40), angiogenesis (9, 21), and coagulation (41).”
BackgroundSelf-citationWound Healing in the PU.1 Null Mouse—Tissue Repair Is Not Dependent on Inflammatory Cells
Martin, P. B., D'Souza, D., Martin, J. S., Grose, R. P., Cooper, L., Maki, R. A., & McKercher, S. R. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00396-8 · Cited by 490 · see citing works
Complement-targeted therapeutics
Ricklin, D., & Lambris, J. D. (2007) · Nature Biotechnology · doi:10.1038/nbt1342 · Cited by 478 · see citing works
Self-citationA two-step fibrinogen–fibrin transition in blood coagulation
Blombäck, B., HESSEL, B., Hogg, D. H., & Therkildsen, L. (1978) · Nature · doi:10.1038/275501a0 · Cited by 476 · cited 1× · see citing works
“Moreover, thrombin, which converts fibrinogen to fibrin (42, 43), is also known to activate complement through the extrinsic pathway by cleaving C5 (6).”
BackgroundSurgical Approaches to Create Murine Models of Human Wound Healing
Wong, V., Sorkin, M., Glotzbach, J. P., Longaker, M. T., & Gurtner, G. C. (2010) · BioMed Research International · doi:10.1155/2011/969618 · Cited by 418 · cited 1× · see citing works
“Although wound healing in a mouse is fundamentally different from that in humans as it primarily occurs via contraction (44), our results show that complement’s beneficiary inhibition targets mechanisms shared between the two species.”
ResultComplement Fragment C3a Controls Mutual Cell Attraction during Collective Cell Migration
Carmona‐Fontaine, C., Théveneau, E., Τζέκου, Α., Tada, M., Woods, M. L., Page, K. M., Parsons, M., Lambris, J. D., & Mayor, R. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.10.012 · Cited by 319 · cited 1× · see citing works
“Inhibition of C3aR was performed as previously described (18).”
MethodSelf-citationComplements and the Wound Healing Cascade: An Updated Review
Sinno, H., & Prakash, S. (2013) · Plastic Surgery International · doi:10.1155/2013/146764 · Cited by 304 · cited 1× · see citing works
“cause the inflammatory response, which is in part regulated by complement components, plays a key role in various stages of wound healing (8).”
BackgroundComplement modulates the cutaneous microbiome and inflammatory milieu
Chehoud, C., Rafail, S., Tyldsley, A. S., Seykora, J. T., Lambris, J. D., & Grice, E. A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1307855110 · Cited by 184 · cited 1× · see citing works
“the bacterial microbiome in the skin of mice through C5aR1 signaling (34).”
BackgroundSelf-citationImmune cells in the healing skin wound: Influential players at each stage of repair
Wilgus, T. A. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.07.009 · Cited by 181 · cited 3× · see citing works
“preventing/fighting infection, the value of certain immune cells in other aspects of repair is now being challenged (3, 28).”
BackgroundThe complement cascade: Yin-Yang in neuroinflammation—neuro-protection and -degeneration
Alexander, J. J., Anderson, A. J., Barnum, S. R., Stevens, B., & Tenner, A. J. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05668.x · Cited by 177 · see citing works
Langer, H. F., Chung, K.-J., Orlova, V. V., Choi, E. Y., Kaul, S., Kruhlak, M. J., Alatsatianos, M., DeAngelis, R. A., Roche, P. A., Magotti, P., et al. (2010) · Blood · doi:10.1182/blood-2010-01-261503 · Cited by 176 · cited 3× · see citing works
“Apart from the role of complement on immune cells, recent work has also shown the involvement of complement in other key processes playing roles in wound healing, such as fibroblast migration and activation (40), angiogenesis (9, 21), and coagulation (41).”
BackgroundMethodResultSelf-citationC1q as a unique player in angiogenesis with therapeutic implication in wound healing
Bossi, F., Tripodo, C., Rizzi, L., Bulla, R., Agostinis, C., Guarnotta, C., Munaut, C., Baldassarre, G., Papa, G., Zorzet, S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311968111 · Cited by 154 · cited 4× · see citing works
“Apart from the role of complement on immune cells, recent work has also shown the involvement of complement in other key processes playing roles in wound healing, such as fibroblast migration and activation (40), angiogenesis (9, 21), and coagulation (41).”
BackgroundMethodInfluentialGoren, I., Müller, E., Schiefelbein, D., Christen, U., Pfeilschifter, J., Mühl, H., & Frank, S. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700842 · Cited by 151 · see citing works
Wound size and gestational age modulate scar formation in fetal wound repair
Cass, D. L., Bullard, K. M., Sylvester, K. G., Yang, E. Y., Longaker, M. T., & Adzick, N. S. (1997) · Journal of Pediatric Surgery · doi:10.1016/s0022-3468(97)90593-5 · Cited by 150 · cited 2× · see citing works
“wound-healing capacity of fetal skin (29).”
BackgroundRegulation of human mast cell and basophil function by anaphylatoxins C3a and C5a
Ali, H. (2009) · Immunology Letters · doi:10.1016/j.imlet.2009.10.007 · Cited by 117 · see citing works
Mast cells and tumour angiogenesis: New insight from experimental carcinogenesis
Crivellato, E., Nico, B., & Ribatti, D. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.03.031 · Cited by 116 · cited 1× · see citing works
“Serine proteases such as chymase degrade the extracellular matrix, and thus prepare the surrounding area for angiogenesis (35).”
BackgroundComplement Activation and Inhibition in Wound Healing
Cazander, G., Jukema, G. N., & Nibbering, P. H. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/534291 · Cited by 110 · see citing works
Recent developments in low molecular weight complement inhibitors
Qu, H., Ricklin, D., & Lambris, J. D. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.08.032 · Cited by 109 · cited 1× · see citing works
“The availability of human complement inhibitors, some of which are currently being tested in clinical trials (45, 46), makes the inhibition of complement activation a promising strategy in promoting faster, safer, and more effective healing.”
BackgroundSelf-citationKashem, S. W., Subramanian, H., Collington, S. J., Magotti, P., Lambris, J. D., & Ali, H. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.06.027 · Cited by 108 · see citing works
Self-citationFang, C., Zhang, X., Miwa, T., & Song, W. (2009) · Blood · doi:10.1182/blood-2009-01-198283 · Cited by 107 · cited 1× · see citing works
“Additionally, recent studies have shown that C1q can regulate the development of dendritic cells from monocytes while affecting T cell stimulation (24), although others have shown that complement promotes Th17 differentiation with the participation of TLRs through C5aR1 signaling (25).”
BackgroundGullstrand, B., Mårtensson, U., Sturfelt, G. K., Bengtsson, A. A., & Truedsson, L. (2009) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2009.03896.x · Cited by 105 · cited 1× · see citing works
“and participate in complement-initiated phagocytosis of intruding entities, whereas they are also involved in the clearance of apoptotic and necrotic cells (22).”
BackgroundGeneration of Anaphylatoxins by Human β-Tryptase from C3, C4, and C5
Fukuoka, Y., Xia, H.-Z., Sánchez‐Muñoz, L., Dellinger, A. L., Escribano, L., & Schwartz, L. B. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.9.6307 · Cited by 101 · see citing works
Leptin and Wound Inflammation in Diabetic<i>ob/ob</i>Mice
Goren, I., Kämpfer, H., Podda, M., Pfeilschifter, J., & Frank, S. (2003) · Diabetes · doi:10.2337/diabetes.52.11.2821 · Cited by 95 · cited 1× · see citing works
“trophils in a mouse model of chronic diabetic wounds also causes faster and improved healing (33).”
BackgroundDefects in Skin γδ T Cell Function Contribute to Delayed Wound Repair in Rapamycin-Treated Mice
Mills, R. E., Taylor, K. R., Podshivalova, K., McKay, D. B., & Jameson, J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.6.3974 · Cited by 79 · see citing works
Pasch, M. C., van den Bosch, N. H. A., Bos, J. D., Asghar, S. S., & Daha, M. R. (2000) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2000.00841.x · Cited by 77 · see citing works
The fibrinogen sequences that interact with thrombin
Binnie, C., & Lord, S. T. (1993) · Blood · doi:10.1182/blood.v81.12.3186.bloodjournal81123186 · Cited by 74 · see citing works
Jalili, A., Shirvaikar, N., Marquez‐Curtis, L. A., Qiu, Y., Korol, C., Lee, H., Turner, A. R., Ratajczak, M. Z., & Janowska‐Wieczorek, A. (2010) · Experimental Hematology · doi:10.1016/j.exphem.2010.02.002 · Cited by 72 · see citing works
Mast Cells Produce Novel Shorter Forms of Perlecan That Contain Functional Endorepellin
Jung, M., Lord, M. S., Cheng, B., Lyons, J. G., Alkhouri, H., Hughes, J. M., McCarthy, S. J., Iozzo, R. V., & Whitelock, J. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.387811 · Cited by 70 · cited 1× · see citing works
“hyaluronic acid, which are proangiogenic (36).”
Teh, B. K., Yeo, J. G., Lai, M. C., & Lu, J. (2011) · Molecular Immunology · doi:10.1016/j.molimm.2011.02.006 · Cited by 68 · cited 1× · see citing works
“Additionally, recent studies have shown that C1q can regulate the development of dendritic cells from monocytes while affecting T cell stimulation (24), although others have shown that complement promotes Th17 differentiation with the participation of TLRs through C5aR1 signaling (25).”
BackgroundThe fibrinogen sequences that interact with thrombin
Binnie, C., & Lord, S. (1993) · Blood · doi:10.1182/blood.v81.12.3186.3186 · Cited by 67 · cited 1× · see citing works
“Moreover, thrombin, which converts fibrinogen to fibrin (42, 43), is also known to activate complement through the extrinsic pathway by cleaving C5 (6).”
BackgroundCole, D. J., HUGHES, T., Gasque, P., & Morgan, B. P. (2006) · Molecular Immunology · doi:10.1016/j.molimm.2005.11.015 · Cited by 62 · see citing works
Kambas, K., Chrysanthopoulou, A., Kourtzelis, I., Skordala, M., Mitroulis, I., Rafail, S., Vradelis, S., Sigalas, I., Wu, Y., Speletas, M. G., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003756 · Cited by 46 · see citing works
Self-citationTopical application of complement C3 in collagen formulation increases early wound healing
Sinno, H., Malholtra, M., Lutfy, J., Jardin, B. A., Winocour, S. J., Brimo, F., Beckman, L., Watters, K. A., Philip, A., Williams, B., et al. (2011) · Journal of Dermatological Treatment · doi:10.3109/09546634.2011.631977 · Cited by 41 · cited 1× · see citing works
“This can also be supported by reports in which C3 treatment increased tensile strength in a rat incision model 3 d after the incision (10).”
BackgroundRole of C5 Activation Products in Sepsis
Ward, P. A. (2010) · The Scientific World JOURNAL · doi:10.1100/tsw.2010.216 · Cited by 41 · cited 1× · see citing works
“C5aR2 in a manner that induces the “cytokine storm” in sepsis (23).”
BackgroundThe effect of complement depletion on wound healing.
Wahl, S. M., Arend, W. P., & Ross, R. (1974) · PubMed · Cited by 35 · see citing works
Neutrophils and natural killer T cells as negative regulators of wound healing
Brubaker, A. L., Schneider, D. F., & Kovacs, E. J. (2011) · Expert Review of Dermatology · doi:10.1586/edm.10.66 · Cited by 35 · cited 1× · see citing works
“preventing/fighting infection, the value of certain immune cells in other aspects of repair is now being challenged (3, 28).”
BackgroundSundberg, J. P., Nanney, L. B., Fleckman, P. H., & King, L. E. (2011) · Elsevier eBooks · doi:10.1016/b978-0-12-381361-9.00023-8 · Cited by 25 · cited 1× · see citing works
“tissue); the last two regions are separated by the panniculus carnosus muscle (19).”
BackgroundA rapid FPLC method for purification of the third component of human and guinea pig complement
Bašta, M., & Hammer, C. H. (1991) · Journal of Immunological Methods · doi:10.1016/0022-1759(91)90290-v · Cited by 22 · cited 1× · see citing works
“C3 was purified from human plasma, as previously described (20), with the following modifications.”
MethodAccelerated Wound Healing with Topical Application of Complement C5
Sinno, H., Malhotra, M., Lutfy, J., Jardin, B. A., Winocour, S. J., Brimo, F., Beckman, L., Watters, K. A., Philip, A., Williams, B., et al. (2012) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0b013e31825dc02d · Cited by 21 · see citing works
To Regeneration ... with Complement
Tsonis, P. A., Lambris, J. D., & Rio‐Tsonis, K. D. (2006) · Advances in experimental medicine and biology · doi:10.1007/0-387-34134-x_5 · Cited by 16 · see citing works
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Complement in disease: a defence system turning offensive
Ricklin, D., Reis, E. S., & Lambris, J. D. (2016) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.70 · Cited by 558 · see citing works
Self-citationNETosis, complement, and coagulation: a triangular relationship
de Bont, C. M., Boelens, W. C., & Pruijn, G. J. M. (2018) · Cellular and Molecular Immunology · doi:10.1038/s41423-018-0024-0 · Cited by 493 · see citing works
Novel mechanisms and functions of complement
Hajishengallis, G., Reis, E. S., Mastellos, D. C., Ricklin, D., & Lambris, J. D. (2017) · Nature Immunology · doi:10.1038/ni.3858 · Cited by 484 · see citing works
Self-citationMaronese, C. A., Pimentel, M. A., Li, M. M., Genovese, G., Ortega‐Loayza, A. G., & Marzano, A. V. (2022) · American Journal of Clinical Dermatology · doi:10.1007/s40257-022-00699-8 · Cited by 221 · see citing works
“In a murine model, C5a has also been shown to have a role in wound healing, with C5a receptor deficiency resulting in more effective wound closure [119].”
BackgroundInflammatory Microenvironment of Skin Wounds
Wang, Z., Qi, F., Luo, H., Xu, G.-C., & Wang, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.789274 · Cited by 202 · see citing works
“In the study of a skin-wound model of C3 or C5 deficient mice, it was found that blocking the complement activation pathway could reduce the intensity of inflammation and accelerate the rate of early healing (78, 79).”
BackgroundThe Insights of Microbes’ Roles in Wound Healing: A Comprehensive Review
Thambirajoo, M., Nurul, A. A., & Fauzi, M. B. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13070981 · Cited by 161 · see citing works
The Biological Processes During Wound Healing
Yang, F., Bai, X., Dai, X., & Li, Y. (2021) · Regenerative Medicine · doi:10.2217/rme-2020-0066 · Cited by 159 · see citing works
The Long Pentraxin PTX3 as a Link Between Innate Immunity, Tissue Remodeling, and Cancer
Doni, A., Stravalaci, M., Inforzato, A., Magrini, E. I., Mantovani, A., Garlanda, C., & Bottazzi, B. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00712 · Cited by 148 · see citing works
Topography-mediated immunomodulation in osseointegration; Ally or Enemy
Shirazi, S., Ravindran, S., & Cooper, L. F. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121903 · Cited by 104 · see citing works
Complement-Dependent Mechanisms and Interventions in Periodontal Disease
Hajishengallis, G., Kajikawa, T., Hajishengallis, E., Maekawa, T., Reis, E. S., Mastellos, D. C., Yancopoulou, D., Hastürk, H., & Lambris, J. D. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00406 · Cited by 95 · see citing works
“This finding is consistent with earlier observations inmice in which C3 deficiency resulted in faster skin wound healing as compared to C3-sufficient control mice (113).”
ResultSelf-citationCellular events during scar‐free skin regeneration in the spiny mouse, Acomys
Brant, J., Yoon, J., Polvadore, T., Barbazuk, W. B., & Maden, M. (2016) · Wound Repair and Regeneration · doi:10.1111/wrr.12385 · Cited by 85 · see citing works
New milestones ahead in complement-targeted therapy
Ricklin, D., & Lambris, J. D. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.06.001 · Cited by 89 · see citing works
Self-citationThe effects of artocarpin on wound healing: in vitro and in vivo studies
Yeh, C.-J., Chen, C., Leu, Y., Lin, M., Chiu, M.-M., & Wang, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-15876-7 · Cited by 84 · see citing works
Chiarelli, N., Ritelli, M., Zoppi, N., & Colombi, M. (2019) · Genes · doi:10.3390/genes10080609 · Cited by 82 · see citing works
“Specifically, C3 functions as a negative regulator of tissue healing, since C3-deficient mice exhibit an increased wound healing and angiogenesis [76].”
BackgroundThe virtuous cycle of human genetics and mouse models in drug discovery
Nadeau, J. H., & Auwerx, J. H. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0009-9 · Cited by 71 · see citing works
Basu, A., Hong, J., & Ferraz, N. (2017) · Macromolecular Bioscience · doi:10.1002/mabi.201700236 · Cited by 60 · see citing works
Ou, M., Tan, P., Xie, Y., Liu, K., Gao, Y., Yang, X., Zhou, S., & Li, Q. (2022) · Theranostics · doi:10.7150/thno.72317 · Cited by 55 · see citing works
“Complement activation, as a part of innate immune system activity, is induced by various tissue injury and is required for wound repair [18].”
BackgroundThe C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets
Nording, H., Baron, L., Haberthür, D., Emschermann, F., Mezger, M., Sauter, M., Sauter, M., Patzelt, J., Knoepp, K., Nording, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23499-w · Cited by 53 · see citing works
Tsao, L.-C., Crosby, E. J., Trotter, T. N., Wei, J.-P., Wang, T., Yang, X. Y., Summers, A. N., Lei, G., Rabiola, C. A., Chodosh, L. A., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.155636 · Cited by 52 · see citing works
“This may be attributable to the activation of complement and local inflammation, which has been demonstrated to suppress wound healing (69, 70).”
Cadmium-induced immune abnormality is a key pathogenic event in human and rat models of preeclampsia
Zhang, Q., Huang, Y., Zhang, K., Huang, Y., Yan, Y., Wang, F., Wu, J., Wang, X., Xu, Z., Chen, Y., et al. (2016) · Environmental Pollution · doi:10.1016/j.envpol.2016.07.073 · Cited by 52 · see citing works
“…that provokes a strong inflammatory response by activation of complement C5a receptors (C5aR) on multiple target cells, including inflammatory cells, endothelial cells, vascular smooth muscle cells, and epithelial cells (Rafail et al., 2015; Li et al., 2015; Shagdarsuren et al., 2010).”
BackgroundSafety profile after prolonged C3 inhibition
Reis, E. S., Berger, N., Wang, X., Koutsogiannaki, S., Doot, R. K., Gumas, J. T., Foukas, P. G., Resuello, R. R. G., Tuplano, J. V., Kukis, D. L., et al. (2018) · Clinical Immunology · doi:10.1016/j.clim.2018.09.004 · Cited by 43 · see citing works
Self-citationVeeser, L. S., & Golubnitschaja, O. (2017) · Journal of Proteomics · doi:10.1016/j.jprot.2017.07.017 · Cited by 41 · see citing works
Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa
Ghias, M. H., Hyde, M. J., Tomalin, L. E., Morgan, B. P., Alavi, A., Lowes, M. A., & Piguet, V. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.09.009 · Cited by 38 · see citing works
Huang, J., & Zhou, Q. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.858972 · Cited by 36 · see citing works
“interactions are essential for the appropriate innate response to retinal injury caused by diabetes, which can limit the development of hyperemia and inflammation while promoting healing (48, 49).”
BackgroundChiarelli, N., Carini, G., Zoppi, N., Ritelli, M., & Colombi, M. (2019) · PLOS ONE · doi:10.1371/journal.pone.0211647 · Cited by 35 · see citing works
The Role of Complement in Angiogenesis
Markiewski, M. M., Daugherity, E. A., Reese, B., & Karbowniczek, M. (2020) · Antibodies · doi:10.3390/antib9040067 · Cited by 35 · see citing works
“The inflammatory infiltrate of wounds was reduced in C3-deficient mice [17].”
BackgroundSelf-citationMuhie, S. Y., Gautam, A., Yang, R., Misganaw, B., Daigle, B. J., Mellon, S. H., Flory, J. D., Amara, D. A., Lee, I., Wang, K., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101045 · Cited by 35 · see citing works
Kourtzelis, I., Magnusson, P., Kotlabová, K., Lambris, J. D., & Chavakis, T. (2015) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-18603-0_11 · Cited by 28 · see citing works
Self-citationAdipose-derived leptin and complement factor D mediate osteoarthritis severity and pain
Collins, K. H., Lenz, K. L., Welhaven, H. D., Ely, E. V., Springer, L. E., Paradi, S. G., Tang, R., Braxton, L. A., Akk, A. M., Yan, H., et al. (2025) · Science Advances · doi:10.1126/sciadv.adt5915 · Cited by 31 · see citing works
Lu, J. D., Milakovic, M., Ortega‐Loayza, A. G., Marzano, A. V., & Alavi, A. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1819981 · Cited by 31 · see citing works
“Accelerated wound healing time was observed in C5a receptor deficient mice.(21)”
BackgroundDoni, A., D’Amico, G., Morone, D., Mantovani, A., & Garlanda, C. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.07.026 · Cited by 30 · see citing works
Allele-specific expression reveals genetic drivers of tissue regeneration in mice
Mack, K. L., desJardins-Park, H. E., Griffin, M., Parker, J. B. L., Guardino, N. J., Spielman, A. F., Davitt, M. F., Mascharak, S., Downer, M. A., Morgan, A. G., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.08.010 · Cited by 32 · see citing works
Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds
Cunnion, K., Krishna, N. K., Pallera, H. K., Piñeros-Fernández, A., Rivera, M., Hair, P., Lassiter, B., Huyck, R., Clements, M., Hood, A., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0170500 · Cited by 28 · see citing works
Mrozikiewicz‐Rakowska, B., Szabłowska‐Gadomska, I., Cysewski, D., Rudziński, S., Płoski, R., Gasperowicz, P., Konarzewska, M., Zieliński, J., Mieczkowski, M., Sieńko, D., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021472 · Cited by 27 · see citing works
Bioactive Medications for the Delivery of Platelet Derivatives to Skin Wounds
Bonferoni, M. C., Rossi, S., Sandri, G., Caramella, C. M., Fante, C. D., Perotti, C. G., Miele, D., Vigani, B., & Ferrari, F. (2019) · Current Drug Delivery · doi:10.2174/1381612825666190320154406 · Cited by 24 · see citing works
“Impaired wound healing can be due to several concomitant conditions such as malnutrition or depression, and pathologies such as chronic inflammation, diabetes mellitus, hormonal dysregulation, vascular diseases and thrombocytopenia related to chronic liver disease [2, 16-18].”
BackgroundHouseright, R. A., Rosowski, E. E., Lam, P., Tauzin, S., Mulvaney, O., Dewey, C. N., Bennin, D., & Anna Huttenlocher, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-72750-9 · Cited by 24 · see citing works
Complement activation links inflammation to dental tissue regeneration
Bergmann, M., Jeanneau, C., Giraud, T., Richard, G., & About, I. (2020) · Clinical Oral Investigations · doi:10.1007/s00784-020-03621-w · Cited by 24 · see citing works
“Complement deficiency has been shown to promote cutaneous wound healing in mice [34].”
BackgroundInsights into the Pathogenesis of Pyoderma Gangrenosum
Becker, S., Vague, M., & Ortega‐Loayza, A. G. (2024) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2024.09.023 · Cited by 23 · see citing works
Complement C3 Exacerbates Imiquimod-Induced Skin Inflammation and Psoriasiform Dermatitis
Giacomassi, C., Buang, N. B., Ling, G. S., Crawford, G., Cook, H. T., Scott, D. M., Dazzi, F., Strid, J., & Botto, M. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.11.011 · Cited by 22 · see citing works
“Furthermore, locally produced C3 contributes to the inflammatory responses accompanying wound healing (Rafail et al., 2014), an effect mediated mainly through C5a/C5aR interactions.”
BackgroundSodhi, E., Philpott, H. T., Carter, M. C., Birmingham, T. B., & Appleton, C. T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.890094 · Cited by 19 · see citing works
“For example, in a model of experimental wound healing, mice deficient in C3, C5, and C5aR1 had better cutaneous wound healing compared to wild-type mice (38).”
BackgroundDNA methylation analysis of negative pressure therapy effect in diabetic foot ulcers
Ludwig‐Słomczyńska, A. H., Borys, S., Seweryn, M. T., Hohendorff, J., Kapusta, P., Kiec-Wilk, B., Pitera, E., Wołkow, P. P., & Malecki, M. T. (2019) · Endocrine Connections · doi:10.1530/ec-19-0373 · Cited by 16 · see citing works
Complement’s involvement in allergic Th2 immunity: a cross-barrier perspective
Thomas, S. A., & Lajoie, S. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188352 · Cited by 14 · see citing works
“However, this pathway is likely tightly regulated, as it can impair wound healing due to overzealous immune cell recruitment (166).”
Padilla, S., Nurden, A. T., Prado, R., Nurden, P., & Anitua, E. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.121205 · Cited by 13 · see citing works
Sasaki, M., Jung, Y., North, P. E., Elsey, J., Choate, K. A., Toussaint, M. A., Huang, C. Y., Radi, R., Perricone, A. J., Corces, V. G., et al. (2022) · Cancers · doi:10.3390/cancers14020413 · Cited by 13 · see citing works
“On the other hand, C5ar1, mutation of which has been shown to increase wound healing in mice [18], shows decreases of chromatin accessibility at the promoter and at two putative enhancers normally bound by Retinoic Acid Receptor gamma (Rarg), Nfya, and Tfap2c (Figure 2E).”
BackgroundNording, H., Baron, L., Sauter, M., Lübken, A., Rawish, E., Szepanowski, F., von Esebeck, J., Sun, Y., Emami, H., Meusel, M., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2021006891 · Cited by 12 · see citing works
Herskind, C., Sticht, C., Sami, A. S., Giordano, F. A., & Wenz, F. K. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.539893 · Cited by 12 · see citing works
Margiotta, F. M., Michelucci, A., Fidanzi, C., Granieri, G., Salvia, G., Bevilacqua, M., Janowska, A., Dini, V., & Romanelli, M. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13144089 · Cited by 13 · see citing works
“It has been shown that C5a receptor-deficient mice presented a more effective wound closure [116] and that bacterial defense, in the absence of C5a, would be more easily achieved through the formation of the membrane attack complex C5b-9 [117].”
BackgroundEzzat, M. I., Abdelhafez, M. M., Al‐Mokaddem, A. K., & Ezzat, S. M. (2025) · Inflammopharmacology · doi:10.1007/s10787-025-01681-6 · Cited by 11 · see citing works
“Controversially, Stav-ros Rafail et al., 2015, reported that complement activation delayed wound healing in a mouse model of wound healing.”
STING Agonist-Induced Skin Inflammation Is Exacerbated with Prior Systemic Innate Immune Activation
Pyclik, M. J., Durślewicz, J., Papinska, J. A., Deshmukh, U. S., & Bagavant, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044128 · Cited by 11 · see citing works
“Considering that complement deficiency improves cutaneous wound healing [18], in our model system, lower Cd55 expression might facilitate complement activation and, thereby, delay wound healing.”
BackgroundWedman, P., Al-Adhami, A., Beste, M., Edwards, M. K., Chumanevich, A. P., Fuseler, J. W., & Oskeritzian, C. A. (2015) · Microscopy and Microanalysis · doi:10.1017/s1431927615015342 · Cited by 9 · see citing works
“Other commonly used histological methods include chloroacetate esterase, but this technique may also stain granulocytes (Rafail et al., 2015).”
MethodIncreased infiltration of CD4+ T cell in the complement deficient lymphedema model
Nishioka, T., Katayama, K., Kumegawa, S., Isono, K., Baba, T., Tsujimoto, H., Yamada, G., Inoue, N., & Asamura, S. (2023) · BMC Immunology · doi:10.1186/s12865-023-00580-1 · Cited by 7 · see citing works
“Furthermore, the deficiency of C3 or C5 has been suggested in a mouse skin model to promote wound healing [17].”
BackgroundTreatment of Pyoderma Gangrenosum With Vilobelimab
Himed, S., Tawfik, H., & Kaffenberger, B. H. (2024) · JAMA Dermatology · doi:10.1001/jamadermatol.2024.1775 · Cited by 8 · see citing works
Proteolytic signaling in cutaneous wound healing
Kalogeropoulos, K., Bundgaard, L., & Keller, U. A. D. (2022) · Proteolytic Signaling in Health and Disease · doi:10.1016/b978-0-323-85696-6.00006-8 · Cited by 1 · see citing works
Critical Role of CD55 in Controlling Wound Healing
Kang, L., Kohen, M. C., McCarthy, I., Hammelef, E., Kim, H. S., Bapputty, R., Gubitosi‐Klug, R., Orge, F. H., Kern, T. S., & Medof, M. E. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2300628 · Cited by 6 · see citing works
Bhutta, M., Sausen, D. G., Reed, K. M., Gallo, E. S., Hair, P. S., Lassiter, B. P., Krishna, N. K., Cunnion, K. M., & Borenstein, R. (2021) · Viruses · doi:10.3390/v13081422 · Cited by 4 · see citing works
“However, elevated levels of complement factors (C3, C5, and membrane attack complex (MAC)) have been reported to cause excessive inflammation, thus delaying the process of healing and leading to the formation of chronic wounds [10,11].”
BackgroundHarnessing blood clot as a native scaffold for orchestrating tissue repairs and regeneration
Dang, G., Wang, Y., Wang, Y., Bai, Q., Hao, J., Li, Z.-T., Cao, X.-Q., Wei, Y., Feng, Y., Chen, J., et al. (2026) · BMEMat · doi:10.1002/bmm2.70101 · Cited by 3 · see citing works
Padilla, S., Prado, R., & Anitua, E. (2023) · BioEssays · doi:10.1002/bies.202300077 · Cited by 2 · see citing works
Yıldırım, C., Albayrak, M. G. B., Yanar, S., Kayır, N., Yozgat, A. H., Aydın, S., & Şahin, F. (2025) · Biomimetics · doi:10.3390/biomimetics10110741 · Cited by 2 · see citing works
“In wound healing contexts, Factor B contributes to C3 convertase formation, supporting debris clearance and inflammation regulation [41].”
Of Salamanders and Spiny Mice: Common Features of Regeneration and Stem Cells
Maden, M. (2017) · Current Stem Cell Reports · doi:10.1007/s40778-017-0086-4 · Cited by 2 · see citing works
[Research advances on inflammatory responses involved in keloid development].
Lei, J., Zhou, Y., & Qin, Z. (2021) · PubMed Central · doi:10.3760/cma.j.cn501120-20200312-00154 · Cited by 2 · see citing works
Hamanaka, R. B., & Mutlu, G. M. (2022) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2022-0268ed · Cited by 2 · see citing works
“Moreover, C3 knockout mice exhibit improved cutaneous wound healing, compared with wild-type mice (6).”
BackgroundWound Healing in Elderly and Frail Patients
Caracino, V., Coletta, P., Palumbo, P., Castiglioni, S., Frazzini, D., & Basti, M. (2021) · Springer eBooks · doi:10.1007/978-3-030-79990-8_6 · Cited by 1 · see citing works
Roles of the Complement System in Peripheral Nerve Injury and Repair
Azar, C., Pan, K., Jain, P., Sánchez‐López, E., & Shah, S. B. (2026) · Bioengineering · doi:10.3390/bioengineering13020251 · Cited by 1 · see citing works
“These all help with clotting as well as recruiting macrophages and fibroblasts to the wound [100,101].”
Al-Jebouri, M. M., & Rasheed, B. Y. (2019) · Open Journal of Pathology · doi:10.4236/ojpathology.2019.92003 · Cited by 1 · see citing works
“The increased angiogenesis and high levels of mast cells contribute to more efficient healing process [30].”
BackgroundComplement C3 as a Target of Host Modulation in Periodontitis
Hajishengallis, G., Kajikawa, T., Hajishengallis, E., Maekawa, T., Li, X., Belibasakis, G. N., Bostancı, N., Mastellos, D. C., Yancopoulou, D., Hastürk, H., et al. (2020) · Springer eBooks · doi:10.1007/978-3-030-42990-4_2 · Cited by 1 · see citing works
Self-citationMuhie, S. Y., Gautam, G., Yang, R., Misganaw, B., Daigle, B. J., Mellon, S. H., Flory, J. D., Amara, D. A., Lee, I., Wang, K., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4160137 · Cited by 1 · see citing works
Welhaven, H. D., Lesnak, J. B., Lenz, K. L., Andoko, B. A., Oestreich, A. K., Plumb, A. N., Sadler, K. E., Springer, L. E., Brockert, J. G., Dumlao, D., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.19.712962 · Cited by 1 · see citing works
THU0256 Complement C3 Exacerbates TLR7-Mediated Skin Inflammation but Not Systemic Autoimmunity
Giacomassi, C., Ling, G. S., Buang, N. B., Strid, J., & Botto, M. (2016) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2016-eular.5720
Allele-specific expression reveals genetic drivers of tissue regeneration in micePreprint
desJardins-Park, H. E., Mack, K. L., Griffin, M., Guardino, N. J., Parker, J. B. L., Spielman, A. F., Davitt, M. F., Mascharak, S., Berger, M. J., Wan, D. C., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.23.509223
“However, prior studies conflict on whether complement activation or inhibition may promote wound healing (Rafail et al., 2015; Sinno et al., 2013), and the effects of complement modulation on scarring have not been investigated.”
BackgroundComplement in chronic wound infections: complementary or a cascade of chaos?
Chamoun, M. N., & Matheus, G. G. (2025) · Microbiology Australia · doi:10.1071/ma25019
Nishioka, T., Katayama, K.-I., Kumegawa, S., Isono, K., Baba, T., Tsujimoto, H., Yamada, G., Inoue, N., & Asamura, S. (2024) · Figshare · doi:10.6084/m9.figshare.24532293
Nishioka, T., Katayama, K.-I., Kumegawa, S., Isono, K., Baba, T., Tsujimoto, H., Yamada, G., Inoue, N., & Asamura, S. (2023) · Figshare · doi:10.6084/m9.figshare.24531959
- Authors
- Rafail, S., Kourtzelis, I., Foukas, P. G., Markiewski, M. M., DeAngelis, R. A., Guariento, M., Ricklin, D., Grice, E. A., & Lambris, J. D.
- Affiliations
- University of Pennsylvania (US)
- Technische Universität Dresden (DE)
- National and Kapodistrian University of Athens (GR)
- Corresponding author
- Rafail, Stavros
- Kourtzelis, Ioannis
- Guariento, Mara
- Ricklin, Daniel
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-01
- Volume
- 194
- Issue
- 3
- Pages
- 1285-1291
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4297721
- OpenAlex
- W1651285952
- Cited by
- 72
- References
- 47
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 11 · 2021: 9 · 2020: 5 · 2019: 9 · 2018: 2 · 2017: 6 · 2016: 6 · 2015: 3
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (n01ai30040-13-0-5, 602699, AI068730, AI030040)
- National Eye Institute (EY020633, R01EY020633)
- National Institute of Allergy and Infectious Diseases (R21AI097805, AI 068730, AI097805, P01AI068730, N01 AI030040, R01AI030040)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R00AR060873)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- complement system, skin wound healing, C3 deficiency, C5a receptor, C5aR1, C5aR2, C3a receptor, C5 deficiency, mast cells, angiogenesis, inflammatory cell infiltration, delayed wound healing, excision wound
- MeSH terms
- Animals, Complement System Proteins, Complement C3, Disease Models, Animal, Humans, Inflammation, Male, Receptors, Complement, Skin, Wound Healing, Complement C5a, Mice, Knockout, Models, Immunological, Neovascularization, Physiologic, Mice
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