CRIg plays an essential role in intravascular clearance of bloodborne parasites by interacting with complement

Abstract

Although CRIg was originally identified as a macrophage receptor for binding complement C3b/iC3b in vitro, recent studies reveal that CRIg functions as a pattern recognition receptor in vivo for Kupffer cells (KCs) to directly bind bacterial pathogens in a complement-independent manner. This raises the critical question of whether CRIg captures circulating pathogens through interactions with complement in vivo under flow conditions. Furthermore, the role of CRIg during parasitic infection is unknown. Taking advantage of intravital microscopy and using African trypanosomes as a model, we studied the role of CRIg in intravascular clearance of bloodborne parasites. Complement C3 is required for intravascular clearance of African trypanosomes by KCs, preventing the early mortality of infected mice. Moreover, antibodies are essential for complement-mediated capture of circulating parasites by KCs. Interestingly, reduced antibody production was observed in the absence of complement C3 during infection. We further demonstrate that CRIg but not CR3 is critically involved in KC-mediated capture of circulating parasites, accounting for parasitemia control and host survival. Of note, CRIg cannot directly catch circulating parasites and antibody-induced complement activation is indispensable for CRIg-mediated parasite capture. Thus, we provide evidence that CRIg, by interacting with complement in vivo, plays an essential role in intravascular clearance of bloodborne parasites. Targeting CRIg may be considered as a therapeutic strategy.

Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis

“…This has been shown by the reduced capture and elimination of S. aureus and L. monocytogenes by the liver KCs in CRIg knock-out mice compared to wild-type mice (Helmy et al, 2006 ). Also, complement opsonization of parasites has been shown to be indispensable for capture and clearance via CRIg by KCs (Liu et al, 2016 ). However, other investigators observed that complement depletion did not affect the capture of gram-positive bacteria, suggesting that CRIg may bind microorganisms directly in a complement-independent manner (Zeng et al, 2016 ).…”

Live Imaging of Innate and Adaptive Immune Responses in the Liver

“…CRIg expression was largely restricted to tissue macrophages, particular in KCs (25,26). This expression profile correlates with the indispensable role of CRIg in KC-mediated immune clearance of various blood-borne microbial species, including parasites (27), fungi (28), and virus (29), all in a complement-dependent manner.…”

Rat IgG mediated circulatory cell depletion in mice requires mononuclear phagocyte system and is facilitated by complement

“…However, taking consideration of the organ size, the liver seems more critical in mediating neutrophil depletion. Moreover, liver KCs represent about 90% of tissue Mϕs and are the major cells to capture circulating bacteria, fungi, and parasites . Thus, we examined the role of the liver during neutrophil depletion using intravital microscopy.…”

“…Moreover, liver KCs represent about 90% of tissue M s 28 and are the major cells to capture circulating bacteria, 29,30 fungi, 31 and parasites. 32 Thus, we examined the role of the liver during neutrophil depletion using intravital microscopy. Under normal conditions, neutrophils traversed the liver sinusoids rapidly with transient or no stoppages (Supplementary Video S1).…”