Modulation of Neutrophil Activity by Soluble Complement Cleavage Products—An In-Depth Analysis

Wohlgemuth, Lisa; Stratmann, Alexander Elias Paul; Münnich, Frederik; Bernhard, Stefan; Thomaß, Bertram Dietrich; Münnich, Finn; Mohamed, Adam Omar Khalaf; Mannes, Marco; Schmidt, Christoph Q.; Ekdahl, Kristina Nilsson; Nilsson, Bo; Fauler, Michael; Föhr, Karl J.; Huber‐Lang, Markus; Messerer, David Alexander Christian

doi:10.3390/cells11203297

Cited by 5 publications

(1 citation statement)

References 49 publications

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“…Finally, we studied the ability of the chimera to inhibit the neutrophil activation upon the exposure to Aspergillus fumigatus conidia. Previous studies have demonstrated that C5a plays a pivotal role in the stimulation of neutrophils via CD11b surface expression, 58 thereby facilitating phagocytosis during fungal infections 59 . Here, we compared MAP‐2:CD55 1‐4 with avacopan.…”

Section: Discussionmentioning

confidence: 99%

MAP‐2:CD55 chimeric construct effectively modulates complement activation

González‐del‐Barrio,

Pérez‐Alós,

Cyranka

et al. 2023

The FASEB Journal

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The complement system is a complex, tightly regulated protein cascade involved in pathogen defense and the pathogenesis of several diseases. Thus, the development of complement modulators has risen as a potential treatment for complement‐driven inflammatory pathologies. The enzymatically inactive MAP‐2 has been reported to inhibit the lectin pathway by competing with its homologous serine protease MASP‐2. The membrane‐bound complement inhibitor CD55 acts on the C3/C5 convertase level. Here, we fused MAP‐2 to the four N‐terminal domains of CD55 generating a targeted chimeric inhibitor to modulate complement activation at two different levels of the complement cascade. Its biological properties were compared in vitro with the parent molecules. While MAP‐2 and CD55 alone showed a minor inhibition of the three complement pathways when co‐incubated with serum (IC50MAP‐2+CD551‐4 = 60.98, 36.10, and 97.01 nM on the classical, lectin, and alternative pathways, respectively), MAP‐2:CD551‐4 demonstrated a potent inhibitory activity (IC50MAP‐2:CD551‐4 = 2.94, 1.76, and 12.86 nM, respectively). This inhibitory activity was substantially enhanced when pre‐complexes were formed with the lectin pathway recognition molecule mannose‐binding lectin (IC50MAP‐2:CD551‐4 = 0.14 nM). MAP‐2:CD551‐4 was also effective at protecting sensitized sheep erythrocytes in a classical hemolytic assay (CH50 = 13.35 nM). Finally, the chimeric inhibitor reduced neutrophil activation in full blood after stimulation with Aspergillus fumigatus conidia, as well as phagocytosis of conidia by isolated activated neutrophils. Our results demonstrate that MAP‐2:CD551‐4 is a potent complement inhibitor reinforcing the idea that engineered fusion proteins are a promising design strategy for identifying and developing drug candidates to treat complement‐mediated diseases.

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Section: Discussionmentioning

confidence: 99%

MAP‐2:CD55 chimeric construct effectively modulates complement activation

González‐del‐Barrio,

Pérez‐Alós,

Cyranka

et al. 2023

The FASEB Journal

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Crepuscular rays — The bright side of complement after tissue injury

Mannes,

Savukoski,

Ignatius

et al. 2024

Eur J Immunol

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Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host‐protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement‐targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance.

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