A naturally occurring transcript variant of MARCO reveals the SRCR domain is critical for function

Abstract

Macrophage receptor with collagenous structure (MARCO) is a Class A Scavenger Receptor (cA-SR) that recognizes and phagocytoses of a wide variety of pathogens. Most cA-SRs that contain a C-terminal Scavenger Receptor Cysteine Rich (SRCR) domain use the proximal collagenous domain to bind ligands. In contrast, for the role of the SRCR domain of MARCO in phagocytosis, adhesion and pro-inflammatory signalling is less clear. The discovery of a naturally-occurring transcript variant lacking the SRCR domain, MARCOII, provided the opportunity to study the role of the SRCR domain of MARCO. We tested whether the SRCR domain is required for ligand binding, promoting downstream signalling, and enhancing cellular adhesion. Unlike cells expressing full-length MARCO, ligand binding was abolished in MARCOII-expressing cells. Furthermore, co-expression of MARCO and MARCOII impaired phagocytic function, indicating that MARCOII acts as a dominant negative variant. Unlike MARCO, expression of MARCOII did not enhance Toll-Like Receptor 2 (TLR2)-mediated pro-inflammatory signalling in response to bacterial stimulation. MARCO-expressing cells were more adherent and exhibited a dendritic-like phenotype, while MARCOII-expressing cells were less adherent and did not exhibit changes in morphology. These data suggest the SRCR domain of MARCO is the key domain in modulating ligand binding, enhancing downstream pro-inflammatory signalling, and MARCO-mediated cellular adhesion.

Airway cells from protracted bacterial bronchitis and bronchiectasis share similar gene expression profiles

“…Some anti‐inflammatory genes such as IL‐10 and CD200R (receptor that limits inflammatory macrophage response) were upregulated in recurrent PBB and bronchiectasis, while TREM2 , an immunoregulatory receptor that can inhibit TLR‐induced macrophage inflammation, was down regulated in both recurrent PBB and bronchiectasis. Both MARCO (scavenger receptor that phagocytose a range of Gram‐positive and Gram‐negative pathogens) and PPAR‐γ (receptor involved in bacteria clearance and resolution of inflammation in macrophages) were down‐regulated in recurrent PBB, and it is possible to speculate that this might be related to a reduced capacity to phagocytose bacteria and clear infections in recurrent PBB. Instead, broader bacterial diversity was linked to lower expression of IL‐10 and CD200R , suggesting that these genes also might be important bacteria clearance regulators in chronic airway diseases, and dysfunction of these genes may result in recurrent PBB or bronchiectasis .…”

The life cycle of phagosomes: formation, maturation, and resolution

“…The active probing described above brings potential targets in contact with the phagocyte surface, where an impressive array of receptors is expressed (for an exhaustive listing of phaogcytic receptors see ). These include receptors like TIM4 and MerTK that recognize homeostatic debris typified by apoptotic cells , and also receptors such as MARCO (macrophage receptor with collagenous structure) that bind bacteria . Importantly, not all phagocytes are created equal: different phagocytes express distinct but overlapping sets of phagocytic receptors, bestowing upon them the capacity to recognize specific targets.…”

Direct binding and internalization of diverse extracellular nucleic acid species through the collagenous domain of class A scavenger receptors

“…SR‐As are highly conserved trimeric molecules containing a short cytoplasmic tail, a transmembrane domain, an α‐helical coiled‐coil domain and a collagenous domain, while several members also contain a C‐terminal cysteine‐rich (SRCR) domain. While the exact mechanism by which these receptors bind a wide range of polyanions is not clearly elucidated, a positively charged lysine cluster within the collagenous domain has been implicated in conformation‐dependent polyanionic ligand binding, while a similar positively charged motif within the SRCR domain may serve in a similar capacity …”