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C4BP(β-)-mediated immunomodulation attenuates inflammation in DSS-induced murine colitis and in myeloid cells from IBD patients

Serrano, Inmaculada ; Luque, Ana ; Ruiz-Cerulla, Alexandra ; Navas, Sergio ; Blom, Anna M. LU orcid ; Rodríguez de Córdoba, Santiago ; Fernández, Francisco J. ; Cristina Vega, M. ; Rodríguez-Moranta, Francisco and Guardiola, Jordi , et al. (2023) In Pharmacological Research 197.
Abstract

The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(β-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(β-)-mediated immunomodulation can... (More)

The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(β-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(β-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(β-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(β-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(β-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to “reprogram” myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD.

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publication status
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subject
keywords
Alpha-D-fructofuranosyl Alpha-D-glucopyranoside (PubChem CID: 3036169), Barium chloride (PubChem CID: 25204), C4BP(β-), Dextran sulfate sodium salt (PubChem CID: 2337), DSS-colitis, Immunomodulation, Inflammation, L-glutamine (PubChem CID: 5961), Minocycline hydrochloride (PubChem CID: 54685925), PRP6-HO7, Sodium dodecyl sulfate (PubChem CID: 3423265), Triton X-100 (PubChem CID: 5590)
in
Pharmacological Research
volume
197
article number
106948
publisher
Academic Press
external identifiers
  • pmid:37806602
  • scopus:85173642197
ISSN
1043-6618
DOI
10.1016/j.phrs.2023.106948
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2023
id
e03fc902-7cb2-4d6e-90b1-b32b282ff244
date added to LUP
2023-11-30 15:55:32
date last changed
2024-04-27 18:51:25
@article{e03fc902-7cb2-4d6e-90b1-b32b282ff244,
  abstract     = {{<p>The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(β-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(β-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(β-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(β-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(β-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to “reprogram” myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD.</p>}},
  author       = {{Serrano, Inmaculada and Luque, Ana and Ruiz-Cerulla, Alexandra and Navas, Sergio and Blom, Anna M. and Rodríguez de Córdoba, Santiago and Fernández, Francisco J. and Cristina Vega, M. and Rodríguez-Moranta, Francisco and Guardiola, Jordi and Aran, Josep M.}},
  issn         = {{1043-6618}},
  keywords     = {{Alpha-D-fructofuranosyl Alpha-D-glucopyranoside (PubChem CID: 3036169); Barium chloride (PubChem CID: 25204); C4BP(β-); Dextran sulfate sodium salt (PubChem CID: 2337); DSS-colitis; Immunomodulation; Inflammation; L-glutamine (PubChem CID: 5961); Minocycline hydrochloride (PubChem CID: 54685925); PRP6-HO7; Sodium dodecyl sulfate (PubChem CID: 3423265); Triton X-100 (PubChem CID: 5590)}},
  language     = {{eng}},
  publisher    = {{Academic Press}},
  series       = {{Pharmacological Research}},
  title        = {{C4BP(β-)-mediated immunomodulation attenuates inflammation in DSS-induced murine colitis and in myeloid cells from IBD patients}},
  url          = {{http://dx.doi.org/10.1016/j.phrs.2023.106948}},
  doi          = {{10.1016/j.phrs.2023.106948}},
  volume       = {{197}},
  year         = {{2023}},
}