Dissimilar and similar functional properties of complement receptor‐3 in microglia and macrophages in combating yeast pathogens by phagocytosis

Abstract

Central nervous system (CNS) microglia (MG) and peripheral tissue macrophages (MO) remove pathogens by phagocytosis. Zymosan, a model yeast pathogen, is a beta-glucan rich particle that readily activates the complement system and then becomes C3bi-opsonized (op). Complement receptor-3 (CR3) has initially been implicated in mediating the phagocytosis of both C3bi-op and non-opsonized (nop) zymosan by MO through C3bi and beta-glucan binding sites, respectively. Later, the role of CR3 as a phagocytic beta-glucan receptor has been questioned and the supremacy of beta-glucan receptor Dectin-1 advocated. We compare here between primary mouse CNS MG and peripheral tissue MO with respect to CR3 and Dectin-1 mediated phagocytosis of C3bi-op and nop zymosan. We report that MG and MO display similar as well as dissimilar functional properties in this respect. Although CR3 and Dectin-1 function both as beta-glucan/non-opsonic receptors in MG during nop zymosan phagocytosis, Dectin-1, but not CR3, does so in MO. CR3 functions also as a C3bi/opsonic receptor in MG and MO during C3bi-op zymosan phagocytosis, leading to phagocytosis which is more efficient than that of nop zymosan. Dectin-1 contributes, albeit less than CR3, to phagocytosis of C3bi-op zymosan in MG and further less in MO, suggesting that C3bi-opsonization does not block all beta-glucan sites on zymosan from binding Dectin-1 on phagocytes. Thus, altogether CR3 and Dectin-1 contribute both to phagocytosis of nop and C3bi-op zymosan in MG, whereas MO switch from CR3-independent/Dectin-1-dependent phagocytosis of nop zymosan to phagocytosis of C3bi-op zymosan where CR3 dominates over Dectin-1.

Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans

“…In addition to β1→3 and β1→6 linkages, fungal glucans contain a small fraction of chitin composed of β1→4 glycosidic linkages (34–36). Both GP and zymosan also contain a small fraction of chitin.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…The complement system regulates the activation of mononuclear phagocytes. The binding of C1q or cleavage products of C3 with the complement receptors on mononuclear phagocytes produce inflammatory cytokines [126,127], and promote phagocytosis of pathogens or apoptotic cells [128][129][130][131].…”

Role of microglia in fungal infections of the central nervous system

“…conidia. 52 On the surface of microglia cells, the TLR-4 predominates, which is known to induce pro-inflammatory processes favoring the development of a Th1 response that is critical in protection against fungi. 53,54 For example, knockout mice for the TLR-4 receptor are susceptible to disseminated candidiasis and reduced clearance of conidias produced by Aspergillus.…”

“…52 Currently, there is limited knowledge on the modulation of anti-inflammatory processes by microglia in the setting of fungal infection. In this regard, stressed mice infected with C. neoformans, stimulate production of anti-inflammatory chemokines such as CCL-2 by microglia, increasing animal susceptibility to disease.…”

“…This slightly differs from macrophages as Dectin-1 predominately mediates phagocytosis of opsonized zymosan, while CR-3 predominates in non-opsonized carbohydrate. 52 Similarly, rodents intracerebrally infected with P. brasiliensis demonstrated progressive neuroinflammation characterized by substantial infiltration of peripheral phagocytic cells and increased chemokine expression that resulted in granulomatous meningoencephalitis. 121 Following the inhalation of conidia, the rare, but invasive pigmented or black fungi, including Cladophialophora bantiana, Exophiala dermatitidis, and Ramichloridium mackenziei, have been isolated as the causative agent of primary cerebral phaeohyphomycosis in individuals with both, competent and compromised immunity lacking medical intervention.…”