Different Trypanosoma cruzi calreticulin domains mediate migration and proliferation of fibroblasts in vitro and skin wound healing in vivo

Arias, J.I.; Parra, Natalia Salinas; Beato, Carolina; Torres, Cristian G.; Hamilton‐West, Christopher; Rosas, Carlos; Ferreira, Arturo

doi:10.1007/s00403-018-1851-7

Cited by 8 publications

(5 citation statements)

References 48 publications

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“…In summary, a greater amount of granulation tissue replete with epidermal appendages was observed in the calreticulin treated excisional mouse wounds (right panels) compared to buffer‐treated controls (left panels). Although there might be subtle differences, the results observed are likely not female‐dependent as another study showed that treatment of male rats with Trypanosoma Cruzi CRT enhanced cutaneous wound healing 53 …”

Section: Resultsmentioning

confidence: 93%

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Calreticulin exploits TGF‐β for extracellular matrix induction engineering a tissue regenerative process

et al. 2020

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Topical application of extracellular calreticulin (eCRT), an ER chaperone protein, in animal models enhances wound healing and induces tissue regeneration evidenced by epidermal appendage neogenesis and lack of scarring. In addition to chemoattraction of cells critical to the wound healing process, eCRT induces abundant neo-dermal extracellular matrix (ECM) formation by 3 days post-wounding. The purpose of this study was to determine the mechanisms involved in eCRT induction of ECM. In vitro, eCRT strongly induces collagen I, fibronectin, elastin, α-smooth muscle actin in human adult dermal (HDFs) and neonatal fibroblasts (HFFs) mainly via TGF-β canonical signaling and Smad2/3 activation; RAP, an inhibitor of LRP1 blocked eCRT ECM induction. Conversely, eCRT induction of α5 and β1 integrins was not mediated by TGF-β signaling nor inhibited by RAP. Whereas eCRT strongly induces ECM and integrin α5 proteins in K41 wild-type mouse embryo fibroblasts (MEFs), CRT null MEFs were unresponsive. The data show that eCRT induces the synthesis and release of TGF-β3 first via LRP1 or other receptor signaling and later induces ECM proteins via LRP1 signaling subsequently initiating TGF-β receptor signaling for intracellular CRT (iCRT)-dependent induction of TGF-β1 and ECM proteins. In addition, TGF-β1 induces 2-3-fold higher level of ECM proteins than eCRT. Whereas eCRT and iCRT converge for ECM induction, we propose that eCRT attenuates TGF-β-mediated fibrosis/scarring to achieve tissue regeneration.

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Section: Resultsmentioning

confidence: 93%

“…Although there might be subtle differences, the results observed are likely not female-dependent as another study showed that treatment of male rats with Trypanosoma Cruzi CRT enhanced cutaneous wound healing. 53…”

Section: Hff 24hmentioning

confidence: 99%

Calreticulin exploits TGF‐β for extracellular matrix induction engineering a tissue regenerative process

et al. 2020

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“…Calr is important in the wound healing process. rTcCalr has been shown to be more effective than HsCalr in this setting, requiring lower concentrations to promote proliferation of fibroblasts, migration of epithelial cells and formation of granulation tissue ( 13 , 148 ). Interestingly, these effects were only observed when the whole protein was administered, suggesting that the protein in its entirety or a large fragment of it is necessary to promote re-epitelization ( 148 ).…”

Section: Calreticulin In Wound Healing and Autoimmunitymentioning

confidence: 99%

The many faces of parasite calreticulin

2023

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Calreticulin from parasites and its vertebrate hosts share ~50% identity and many of its functions are equally conserved. However, the existing amino acid differences can affect its biological performance. Calreticulin plays an important role in Ca2+ homeostasis and as a chaperone involved in the correct folding of proteins within the endoplasmic reticulum. Outside the endoplasmic reticulum, calreticulin is involved in several immunological functions such as complement inhibition, enhancement of efferocytosis, and immune upregulation or inhibition. Several parasite calreticulins have been shown to limit immune responses and promote infectivity, while others are strong immunogens and have been used for the development of potential vaccines that limit parasite growth. Furthermore, calreticulin is essential in the dialogue between parasites and hosts, inducing Th1, Th2 or regulatory responses in a species-specific manner. In addition, calreticulin participates as initiator of endoplasmic reticulum stress in tumor cells and promotion of immunogenic cell death and removal by macrophages. Direct anti-tumoral activity has also been reported. The highly immunogenic and pleiotropic nature of parasite calreticulins, either as positive or negative regulators of the immune response, render these proteins as valuable tools to modulate immunopathologies and autoimmune disorders, as well as a potential treatment of neoplasms. Moreover, the disparities in the amino acid composition of parasite calreticulins might provide subtle variations in the mechanisms of action that could provide advantages as therapeutic tools. Here, we review the immunological roles of parasite calreticulins and discuss possible beneficial applications.

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“…These cells can be engulfed by macrophages and dendritic cells co-cultured with rTcCalr, accelerating its maturation and activating T cells ( 100 ). Similar to its human counterpart, TcCalr promotes wound healing in rats ( 101 ); however, whether this property correlates with the known anti-complement capacity of the parasite chaperone, is unknown.…”

Section: Other Tccalr Functions In the Host-parasite Interplaymentioning

confidence: 99%

The Interactions of Parasite Calreticulin With Initial Complement Components: Consequences in Immunity and Virulence

et al. 2020

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Because of its capacity to increase a physiologic inflammatory response, to stimulate phagocytosis, to promote cell lysis and to enhance pathogen immunogenicity, the complement system is a crucial component of both the innate and adaptive immune responses. However, many infectious agents resist the activation of this system by expressing or secreting proteins with a role as complement regulatory, mainly inhibitory, proteins. Trypanosoma cruzi, the causal agent of Chagas disease, a reemerging microbial ailment, possesses several virulence factors with capacity to inhibit complement at different stages of activation. T. cruzi calreticulin (TcCalr) is a highly-conserved, endoplasmic reticulum-resident chaperone that the parasite translocates to the extracellular environment, where it exerts a variety of functions. Among these functions, TcCalr binds C1, MBL and ficolins, thus inhibiting the classical and lectin pathways of complement at their earliest stages of activation. Moreover, the TcCalr/C1 interaction also mediates infectivity by mimicking a strategy used by apoptotic cells for their removal. More recently, it has been determined that these Calr strategies are also used by a variety of other parasites. In addition, as reviewed elsewhere, TcCalr inhibits angiogenesis, promotes wound healing and reduces tumor growth. Complement C1 is also involved in some of these properties. Knowledge on the role of virulence factors, such as TcCalr, and their interactions with complement components in host-parasite interactions, may lead toward the description of new anti-parasite therapies and prophylaxis.

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Different Trypanosoma cruzi calreticulin domains mediate migration and proliferation of fibroblasts in vitro and skin wound healing in vivo

Cited by 8 publications

References 48 publications

Calreticulin exploits TGF‐β for extracellular matrix induction engineering a tissue regenerative process

Calreticulin exploits TGF‐β for extracellular matrix induction engineering a tissue regenerative process

The many faces of parasite calreticulin

The Interactions of Parasite Calreticulin With Initial Complement Components: Consequences in Immunity and Virulence

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