C1q as a unique player in angiogenesis with therapeutic implication in wound healing

Bossi, Fleur; Tripodo, Claudio; Rizzi, Lucia; Bulla, Roberta; Agostinis, Chiara; Guarnotta, Carla; Munaut, Carine; Baldassarre, Gustavo; Papa, Giovanni; Zorzet, Sonia; Ghebrehiwet, Berhane; Ling, Guang Sheng; Botto, Marina; Tedesco, Francesco

doi:10.1073/pnas.1311968111

Cited by 134 publications

(140 citation statements)

References 28 publications

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“…Because angiogenesis plays a key role in wound healing and complement has been suggested to be involved in angiogenesis (9, 21), we stained wounded tissue sections with an antibody against α-SMA to assess vascularization. We detected significantly increased numbers of α-SMA + vessels in the hypodermis of C3 −/− mice compared to C3 +/+ mice (p=0.001) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Complement Deficiency Promotes Cutaneous Wound Healing in Mice

Rafail

Kourtzelis

Foukas

et al. 2015

The Journal of Immunology

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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. Here 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 to 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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Section: Resultsmentioning

confidence: 99%

Complement Deficiency Promotes Cutaneous Wound Healing in Mice

Rafail

Kourtzelis

Foukas

et al. 2015

The Journal of Immunology

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“…For example, C1q has been reported to play an important role in nerve pruning (Stevens et al, 2007) Wnt/Beta-catenin signalling (Naito et al, 2012;Sumida et al, 2015). Also a role for C1q was reported on neoangiogenesis (Bossi et al, 2014).…”

Section: C1q Traditional and Non-traditional Rolesmentioning

confidence: 99%

C1q, antibodies and anti-C1q autoantibodies

Beurskens

Schaarenburg

Trouw

2015

Molecular Immunology

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“…Recent studies have demonstrated its involvement in several physiological processes via binding with its specific receptors. 9 Among the processes induced by the non-classical functions of the C1q molecule, we find: the modulation of various immune cells, 10 the regulation of cell migration (chemotaxis), adhesion, survival and differentiation, 11 coagulation, 12 angiogenesis 13 and embryonic development, including neurological synapse function. 14 There is mounting evidence to support the idea that C1q and its receptors are also involved in the regulation of cancer.…”

Section: Introductionmentioning

confidence: 95%

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

et al. 2016

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There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu C carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation.Abbreviations: BALB-C1KO, BALB/c mice deficient for the C1qA; BALB-C3KO, BALB/c mice deficient for C3; C1KO, C1q deficient; C1qR, C1q receptor; CR3, complement receptor 3; EMT, epithelial-to-mesenchymal transition; KLRK1 or NKG2D, killer cell lectin-like receptor subfamily K, member 1; MDCS, myeloid-derived suppressor cells; neuT, rat Her2/neu transgenic; neuT-BKO mice, neuT mice deficient in antibody production; neuT-C1KO mice, neuT mice deficient for the C1qA molecule; neuT-C3KO mice, neuT mice deficient for the C3 molecule; NK, natural killer; pWWOX, phospho WWOX; Treg, T regulatory; WWOX, WW domain containing oxidoreductase

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C1q as a unique player in angiogenesis with therapeutic implication in wound healing

Cited by 134 publications

References 28 publications

Complement Deficiency Promotes Cutaneous Wound Healing in Mice

Complement Deficiency Promotes Cutaneous Wound Healing in Mice

C1q, antibodies and anti-C1q autoantibodies

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

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