Local complement activation and modulation in mucosal immunity

Kulkarni, Devesha H.; Starick, Marick; Aponte Alburquerque, Rafael; Kulkarni, Hrishikesh S.

doi:10.1016/j.mucimm.2024.05.006

Mucosal Immunology

2024

DOI: 10.1016/j.mucimm.2024.05.006

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Local complement activation and modulation in mucosal immunity

Devesha H. Kulkarni,

Marick Starick,

Rafael Aponte Alburquerque

et al.

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2024

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Cited by 2 publications

References 147 publications

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The C3-C3aR axis modulates trained immunity in alveolar macrophages

Earhart,

Alburquerque,

Starick

et al. 2024

Preprint

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Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity (enhanced secondary responses of innate immune cells after prior exposure) is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that in vivo, trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury. Ex vivo, C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output after training, which was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs; a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling, affecting cytokine production and metabolic reprogramming, and highlight a novel role for C3 in trained immunity.

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The C3-C3aR axis modulates trained immunity in alveolar macrophages

Earhart,

Alburquerque,

Starick

et al. 2024

Preprint

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Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

Kulkarni,

Tague,

Calabrese

et al. 2024

Preprint

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A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation, is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early post-lung transplantation to form the C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3R102G) that increases complement activation through impaired C3 convertase inactivation in two independent LTx recipient cohorts. C3R102G, identified in at least one out of three LTx recipients, was associated with worse CLAD-free survival, particularly in the subset of recipients who developed donor-specific antibodies (DSA). In a mouse orthotopic lung transplantation model, impaired recipient complement regulation resulted in more severe obstructive airway lesions when compared to wildtype controls, despite only moderate differences in graft-infiltrating effector T cells. Impaired complement regulation promoted the intragraft accumulation of memory B cells and antibody-secreting cells, resulting in increased DSA levels. In summary, genetic predisposition to complement activation is associated with B cell activation and worse CLAD-free survival.

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Local complement activation and modulation in mucosal immunity

Cited by 2 publications

References 147 publications

The C3-C3aR axis modulates trained immunity in alveolar macrophages

The C3-C3aR axis modulates trained immunity in alveolar macrophages

Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

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