Anti-inflammatory effects of haptoglobin on LPS-stimulated macrophages: Role of HMGB1 signaling and implications in chronic wound healing.
Animals
Antigens, CD
/ metabolism
Antigens, Differentiation, Myelomonocytic
/ metabolism
Diabetes Mellitus
HMGB1 Protein
/ drug effects
Haptoglobins
/ pharmacology
Heme Oxygenase-1
Hemoglobins
/ pharmacology
Humans
Inflammation
/ metabolism
Lipopolysaccharides
/ pharmacology
Macrophages
/ drug effects
Mice
Mice, Obese
Receptors, Cell Surface
/ metabolism
Signal Transduction
Wound Healing
/ drug effects
Journal
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
ISSN: 1524-475X
Titre abrégé: Wound Repair Regen
Pays: United States
ID NLM: 9310939
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
09
07
2019
revised:
15
03
2020
accepted:
24
03
2020
pubmed:
20
5
2020
medline:
22
7
2021
entrez:
20
5
2020
Statut:
ppublish
Résumé
Nonhealing wounds possess elevated numbers of pro-inflammatory M1 macrophages, which fail to transition to anti-inflammatory M2 phenotypes that promote healing. Hemoglobin (Hb) and haptoglobin (Hp) proteins, when complexed (Hb-Hp), can elicit M2-like macrophages through the heme oxygenase-1 (HO-1) pathway. Despite the fact that nonhealing wounds are chronically inflamed, previous studies have focused on non-inflammatory systems, and do not thoroughly compare the effects of complexed vs individual proteins. We aimed to investigate the effect of Hb/Hp treatments on macrophage phenotype in an inflammatory, lipopolysaccharide (LPS)-stimulated environment, similar to chronic wounds. Human M1 macrophages were cultured in vitro and stimulated with LPS. Concurrently, Hp, Hb, or Hb-Hp complexes were delivered. The next day, 27 proteins related to inflammation were measured in the supernatants. Hp treatment decreased a majority of inflammatory factors, Hb increased many, and Hb-Hp had intermediate trends, indicating that Hp attenuated overall inflammation to the greatest extent. From this data, Ingenuity Pathway Analysis software identified high motility group box 1 (HMGB1) as a key canonical pathway-strongly down-regulated from Hp, strongly up-regulated from Hb, and slightly activated from Hb-Hp. HMGB1 measurements in macrophage supernatants confirmed this trend. In vivo results in diabetic mice with biopsy punch wounds demonstrated accelerated wound closure with Hp treatment, and delayed wound closure with Hb treatment. This work specifically studied Hb/Hp effects on macrophages in a highly inflammatory environment relevant to chronic wound healing. Results show that Hp-and not Hb-Hp, which is known to be superior in noninflammatory conditions-reduces inflammation in LPS-stimulated macrophages, and HMGB1 signaling is also implicated. Overall, Hp treatment on M1 macrophages in vitro reduced the inflammatory secretion profile, and also exhibited benefits in in silico and in vivo wound-healing models.
Substances chimiques
Antigens, CD
0
Antigens, Differentiation, Myelomonocytic
0
CD163 antigen
0
HMGB1 Protein
0
Haptoglobins
0
Hemoglobins
0
Lipopolysaccharides
0
Receptors, Cell Surface
0
haptoglobin-hemoglobin complex
0
Heme Oxygenase-1
EC 1.14.14.18
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
493-505Subventions
Organisme : NIGMS NIH HHS
ID : NIH T32 GM008339
Pays : United States
Organisme : NIH HHS
ID : R01EB021926
Pays : United States
Organisme : NIH HHS
ID : R01HL126945
Pays : United States
Organisme : NIH HHS
ID : R01HL138116
Pays : United States
Informations de copyright
© 2020 by the Wound Healing Society.
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