Citryll has published new preclinical research that deepens the understanding of how CIT-013, the Company’s first-in-class monoclonal antibody, modulates immune responses in inflammatory disease. The study shows that CIT-013 not only enhances the clearance of extracellular traps (ETs), but also modulates macrophage behaviour to promote the resolution of inflammation. Targeting the citrullinated histone component of ETs represents a promising, novel therapeutic strategy, with ET clearance identified as a critical determinant of inflammation resolution.
Study background: The role of macrophages in ET-driven inflammation
ETs are web-like structures released by white blood cells as part of the innate immune response to pathogens, pro-inflammatory and tissue damage-related signals, whose persistent accumulation in tissues is increasingly recognised as a driver of chronic inflammation, cytotoxicity, and tissue damage in immune-mediated inflammatory diseases (IMIDs).
Macrophages, a key cell type of the innate immune system, play an important role in clearing ETs through phagocytosis, the process by which cells engulf and remove unwanted material. However, macrophages are not all the same, and ET clearance is not uniformly efficient across macrophage subsets. In chronically inflamed tissues, pro-inflammatory macrophages tend to be the dominant phenotype, and this study shows that these cells have a limited ability to clear ETs, allowing inflammatory material to persist.
By contrast, a distinct phenotype of macrophages known as inflammation-resolving macrophages are much more efficient at phagocytosing ETs and supporting tissue recovery in IMIDs. The imbalance of macrophage subtypes in chronically inflamed tissue, characterized by an increased prevalence of pro-inflammatory macrophages and reduced inflammation-resolving macrophage activity, contributes to inefficient ET clearance, local ET accumulation and exacerbation of inflammation and tissue damage, highlighting an opportunity to enhance inflammatory resolution by engaging macrophages that are otherwise less active in this process.
Study findings: How CIT-013 changes macrophage behaviour and chemokine signalling
This study explored what happens when ETs are bound by CIT-013 in a process known as opsonisation, effectively “tagging” a target so that it can be more readily recognised and cleared by immune cells.
When ETs were opsonised with CIT-013, phagocytic uptake increased significantly across macrophage populations. Importantly, pro-inflammatory macrophages which normally struggle to clear ETs gained the ability to efficiently engulf them, representing a shift toward an inflammation-resolving behaviour that these cells do not typically display.
These findings reveal a previously unrecognised regulatory mechanism: CIT-013 opsonisation of ETs can reprogram and regulate macrophage responses, rather than simply marking inflammatory material for removal.
Beyond its effects on macrophage-mediated clearance, the study also highlights a broader immunological impact of CIT-013 through modulation of chemokine signalling. Chemokines are a group of small signaling proteins that act as chemical messengers for immune cells, guiding them to specific locations in the body, especially to sites of infection or inflammation. They serve as a key interface between the innate immune system and the adaptive immune system.
The data show that opsonisation of ETs with CIT-013 reduces the release of chemokines involved in T-cell recruitment to sites of inflammation, while simultaneously boosting the release of the anti-inflammatory cytokine IL-10. Together, these changes diminish macrophage signals associated with T-cell recruitment and activation, shifting the response toward dampening inflammation. CIT-013 may therefore shape not only local innate immune activity but also the downstream engagement of adaptive immune responses.
Study implications: What this means for CIT-013 in inflammatory disease
CIT-013 has previously been shown to act through a dual mechanism of action – inhibiting ET formation and enhancing macrophage-mediated ET clearance. This new research deepens our understanding of the consequences of this mechanism of action.
These findings suggest that CIT-013-mediated ET opsonisation can produce broader immunomodulatory effects that favour reduced inflammatory signalling, providing additional mechanistic rationale for targeting ET-driven inflammation.
See the full manuscript here: Frontiers | Antibody-opsonized extracellular traps modulate macrophage responses and attenuate their T cell-associated inflammatory and costimulatory characteristics