Pulmonary intravascular macrophages: prime suspects as cellular mediators of porcine CARPA

Abstract

Pigs provide a highly sensitive and quantitative in vivo model for complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction caused by some state-of-art nanomedicines. In an effort to understand the mechanism of the pigs' unique sensitivity for CARPA, this review focuses on pulmonary intravascular macrophages (PIMs), which are abundantly present in the lung of pigs. These cells represent a macrophage subpopulation whose unique qualities explain the characteristic symptoms of CARPA in this species, most importantly the rapidly (within minutes) developing pulmonary vasoconstriction, leading to elevation of pulmonary arterial pressure. The unique qualities of PIM cells include the following; 1) they are strongly adhered to the capillary walls via desmosome-like intercellular adhesion plaques, which secure stable and lasting direct exposition of the bulk of these cells to the blood stream; 2) their ruffled surface engaged in intense phagocytic activity ensures efficient binding and phagocytosis of nanoparticles; 3) PIM cells express anaphylatoxin receptors, this way C activation can trigger these cells, 4) they also express pattern recognition molecules on their surface, whose engagement with certain coated nanoparticles may also activate these cells or act in synergy with anaphylatoxins and, finally 5) their high metabolic activity and capability for immediate secretion of vasoactive mediators upon stimulation explain the circulatory blockage and other robust physiological effects that their stimulation may cause. These qualities taken together with reports on liposome uptake by PIM cells during CARPA and the possible presence of these cells in human lung suggests that PIM cells may be a potential therapeutic target against CARPA.Keywords: adverse immune effects; anaphylatoxins; anaphylaxis; complement; hypersensitivity reactions; nanomedicines; pulmonary intravascular macrophages Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.

PTX3 activates classic complement pathway and mediates phagocytosis of cholesterol-induced apoptotic macrophages in atherosclerosis

“…PTX3 is produced obviously by macrophages and endothelial cells in advanced atherosclerotic lesions [2,5]. Mice lacking PTX3 showed more pronounced inflammatory profile in the vascular wall, an increased macrophage accumulation within the plaque, a greater noreflow area in a model of acute myocardial infarction, however, all of which could be reversed by exogenous PTX3 [6,7]. The above data support the cardio-protective function of PTX3.…”

“…C3b/C4b on desialated sheep erythrocytes involved in their phagocytosis when binding on C3b/C4b receptor (CR1) on macrophages. The process was inhibited by treating macrophages with a monoclonal antibody to CR1 [7,26,27]. We also observed that C3b played an important part in efferocytosis of FC-AMs, however, which was inhibited by a monoclonal antibody of C3b.…”

A porcine model of complement activation-related pseudoallergy to nano-pharmaceuticals: Pros and cons of translation to a preclinical safety test

“…The abundant presence of PIMs is observed only in a few species, such as sheep, cattle, horse, and cat (36). Their function is to screen the blood from particulate pathogens (37)(38)(39)(40)(41). PIM cells express anaphylatoxin C5a receptor (ATR, C5aR) on their surface as well as Fc, Toll like-and C receptors (CR1, CR3 and CR4), and can secrete vasoactive mediators including TxA2, histamine, leukotrienes, PAF, and IL-6, IL-8 and IL-1β).…”

“…PIM cells express anaphylatoxin C5a receptor (ATR, C5aR) on their surface as well as Fc, Toll like-and C receptors (CR1, CR3 and CR4), and can secrete vasoactive mediators including TxA2, histamine, leukotrienes, PAF, and IL-6, IL-8 and IL-1β). The combination of different vasoactivity of all secretion products explains the versatility of systemic blood pressure changes in CARPA (40). However, TxA2 and many of these mediators may also be released by other ATR+ cells, including mast cells, leukocytes and activated platelets (42).…”

“…The mechanism underlying CARPA, in general, and tachyphylaxis, in particular, are poorly understood. The "double hit" theory (5,27,40) mentioned above in the context of PIM cells, postulates that NPs can induce HSRs by simultaneous stimulation of anaphylatoxin receptors (mainly C5aR, CD88) and other surface receptors on PIM cells, which can be linked to release reactions directly or indirectly. Potential receptors include pathogen recognition receptors, also known as pathogen-associated molecular pattern receptors (51,52), mannose-binding lectin receptor (53,54), C receptors (CR2 and CR3 and Fc receptors) (55) and many others typically present on the surface of mast cells (56,57).…”