Cell-intrinsic C5a synergizes with Dectin-1 in macrophages to mediate fungal killing.
Proc Natl Acad Sci U S A
; 121(5): e2314627121, 2024 Jan 30.
Article
in En
| MEDLINE
| ID: mdl-38252818
ABSTRACT
The complement factor C5a is a core effector product of complement activation. C5a, acting through its receptors C5aR1 and C5aR2, exerts pleiotropic immunomodulatory functions in myeloid cells, which is vital for host defense against pathogens. Pattern-recognition receptors (PRRs) are similarly expressed by immune cells as detectors of pathogen-associated molecular patterns. Although there is evidence of cross talk between complement and PRR signaling pathways, knowledge of the full potential for C5a-PRR interaction is limited. In this study, we comprehensively investigated how C5a signaling through C5a receptors can modulate diverse PRR-mediated cytokine responses in human primary monocyte-derived macrophages and observed a powerful, concentration-dependent bidirectional effect of C5a on PRR activities. Unexpectedly, C5a synergized with Dectin-1, Mincle, and STING in macrophages to a much greater extent than TLRs. Notably, we also identified that selective Dectin-1 activation using depleted zymosan triggered macrophages to generate cell-intrinsic C5a, which acted on intracellular and cell surface C5aR1, to help sustain mitochondrial ROS generation, up-regulate TNFα production, and enhance fungal killing. This study adds further evidence to the holistic functions of C5a as a central immunomodulator and important orchestrator of pathogen sensing and killing by phagocytes.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Complement C5a
/
Lectins, C-Type
/
Macrophages
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2024
Document type:
Article
Affiliation country:
Australia
Country of publication:
Estados Unidos