Canonical and non‐canonical functions of the complement system in health and disease

Wenzel, Ulrich; Kemper, Claudia; Köhl, Jörg

doi:10.1111/bph.15503

Cited by 6 publications

(6 citation statements)

References 21 publications

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“…Whether the complement system, a major innate and inflammatory effector system, contributes to hypertensive end-organ damage is still unresolved (Wenzel, Ehmke, & Bode, 2021;Wenzel, Kemper, & Köhl, 2021). The current study provides novel insights into the role of complement in hypertensive end-organ damage.…”

Section: Discussionmentioning

confidence: 91%

“…The innate and adaptive immune system are increasingly recognized to play a decisive role in the pathophysiology of arterial hypertension and hypertension‐induced end organ damage (Wenzel et al, 2016). Whether the complement system, a major innate and inflammatory effector system, contributes to hypertensive end‐organ damage is still unresolved (Wenzel, Ehmke, & Bode, 2021; Wenzel, Kemper, & Köhl, 2021). The current study provides novel insights into the role of complement in hypertensive end‐organ damage.…”

Section: Discussionmentioning

confidence: 99%

“…The increasing number of clinical conditions that involve a pathological contribution of the complement system has spurred a regained interest in therapeutic options to modulate this host defence pathway. Based on these findings, the pharmaceutical industry has identified the complement system as potential and promising targets in various diseases (Wenzel, Kemper, & Köhl, 2021). The complement system protects the host from a hostile microbial environment and maintains tissue and cell integrity through the elimination of altered or dead cells.…”

Section: Introductionmentioning

confidence: 99%

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Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease

Bode

Diemer

Luu

et al. 2023

British J Pharmacology

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Background and PurposeComplement activation may drive hypertension through its effects on immunity and tissue integrity.Experimental ApproachWe examined expression of C3, the central protein of the complement cascade, in hypertension.Key ResultsIncreased C3 expression was found in kidney biopsies and micro‐dissected glomeruli of patients with hypertensive nephropathy. Renal single cell RNA sequence data from normotensive and hypertensive patients confirmed expression of C3 in different cellular compartments of the kidney. In angiotensin II (Ang II) induced hypertension renal C3 expression was up‐regulated. C3−/− mice revealed a significant lower albuminuria in the early phase of hypertension. However, no difference was found for blood pressure, renal injury (histology, glomerular filtration rate, inflammation) and cardiac injury (fibrosis, weight, gene expression) between C3−/− and wildtype mice after Ang II infusion. Also, in deoxycorticosterone acetate (DOCA) salt hypertension, a significantly lower albuminuria was found in the first weeks of hypertension in C3 deficient mice but no significant difference in renal and cardiac injury. Down‐regulation of C3 by C3 targeting GalNAc (n‐acetylgalactosamine) small interfering RNA (siRNA) conjugate decreased C3 in the liver by 96% and lowered albuminuria in the early phase but showed no effect on blood pressure and end‐organ damage. Inhibition of complement C5 by siRNA showed no effect on albuminuria.Conclusion and ImplicationsIncreased C3 expression is found in the kidneys of hypertensive mice and men. Genetic and therapeutic knockdown of C3 improved albuminuria in the early phase of hypertension but did not ameliorate arterial blood pressure nor renal and cardiac injury.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease

Bode

Diemer

Luu

et al. 2023

British J Pharmacology

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“…The large number of pathological conditions in which the complement system is involved has stimulated the development of therapeutic interventions [ 13 ]. Thus, various components of this system, such as the anaphylatoxins and their receptors, have been considered promising therapeutic targets in inflammatory diseases [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Complement System Inhibitory Drugs in a Zebrafish (Danio rerio) Model: Computational Modeling

Fernandes,

Tambourgi

2023

IJMS

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The dysregulation of complement system activation usually results in acute or chronic inflammation and can contribute to the development of various diseases. Although the activation of complement pathways is essential for innate defense, exacerbated activity of this system may be harmful to the host. Thus, drugs with the potential to inhibit the activation of the complement system may be important tools in therapy for diseases associated with complement system activation. The synthetic peptides Cp40 and PMX205 can be highlighted in this regard, given that they selectively inhibit the C3 and block the C5a receptor (C5aR1), respectively. The zebrafish (Danio rerio) is a robust model for studying the complement system. The aim of the present study was to use in silico computational modeling to investigate the hypothesis that these complement system inhibitor peptides interact with their target molecules in zebrafish, for subsequent in vivo validation. For this, we analyzed molecular docking interactions between peptides and target molecules. Our study demonstrated that Cp40 and the cyclic peptide PMX205 have positive interactions with their respective zebrafish targets, thus suggesting that zebrafish can be used as an animal model for therapeutic studies on these inhibitors.

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“…Aside from its well-appreciated canonical activation pathways, non-canonical mechanisms have been recently described, which orchestrate the cleavage and activation of complement factors both in the circulation and intracellularly in immune cells ( 2 ). The broad implications of complement activation for health and disease have been reviewed elsewhere ( 3 ). Canonical complement activation occurs via three different pathways, i.e., the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP), all of which converge at the level of C3, eventually resulting in terminal pathway (TP) activation and subsequent membrane attack complex (MAC) formation ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Anaphylatoxins spark the flame in early autoimmunity

2022

Self Cite

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The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to specific receptors on innate and adaptive immune cells, the activation of which translates the initial humoral innate immune response (IR) into cellular innate and adaptive immunity. Dysregulation of the CS has been associated with the development of several autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis, and autoimmune bullous dermatoses (AIBDs), where complement drives the inflammatory response in the effector phase. The role of the CS in autoimmunity is complex. On the one hand, complement deficiencies were identified as risk factors to develop autoimmune disorders. On the other hand, activation of complement can drive autoimmune responses. The anaphylatoxins C3a and C5a are potent mediators and regulators of inflammation during the effector phase of autoimmunity through engagement of specific anaphylatoxin receptors, i.e., C3aR, C5aR1, and C5aR2 either on or in immune cells. In addition to their role in innate IRs, anaphylatoxins regulate humoral and cellular adaptive IRs including B-cell and T-cell activation, differentiation, and survival. They regulate B- and T-lymphocyte responses either directly or indirectly through the activation of anaphylatoxin receptors via dendritic cells that modulate lymphocyte function. Here, we will briefly review our current understanding of the complex roles of anaphylatoxins in the regulation of immunologic tolerance and the early events driving autoimmunity and the implications of such regulation for therapeutic approaches that target the CS.

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Canonical and non‐canonical functions of the complement system in health and disease

Cited by 6 publications

References 21 publications

Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease

Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease

Complement System Inhibitory Drugs in a Zebrafish (Danio rerio) Model: Computational Modeling

Anaphylatoxins spark the flame in early autoimmunity

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