Brugia malayi Microfilariae Induce a Regulatory Monocyte/Macrophage Phenotype That Suppresses Innate and Adaptive Immune Responses

Abstract

BackgroundMonocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive.AimTo determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses.Methodology and principal findingsMonocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner.Conclusions and significanceConclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients.

Host lung immunity is severely compromised during tropical pulmonary eosinophilia: role of lung eosinophils and macrophages

“…This was an unexpected finding, because CCL2 has been shown to exert its protective role in the activation of macrophages and induction of eosinophilia [34]. However, this observation could have resulted from either filaria-induced monocyte dysfunction [35,36], or induction of a regulatory monocyte/macrophage phenotype which suppresses innate and adaptive immune responses in B. malayi-infected animals [37]. However, as expected, reduced monocyte counts corroborated with reduced AMF in the lungs of TPE mice, which might have resulted from either impaired differentiation of monocytes into macrophages or early apoptosis of macrophages during filarial infection.…”

Looking beyond the induction of Th2 responses to explain immunomodulation by helminths

“…While helminth infection does induce the expression of these AAMs and other regulatory monocyte/macrophage populations in humans (83)(84)(85)(86), the primary functional consequence of having increased frequencies of these cells is interference with full T-cell activation (86,87).…”

Vasoactive intestinal peptide is required in the maintenance of immune regulatory competency of immune regulatory monocytes

“…Although the RegMo frequency is comparable between HC subjects and RA patients, the immune regulatory function of RegMos is impaired in the RA group. Such activities were found in monocytes upon exposure to microbial products [21]; B regs can also suppress other immune cell activities upon correct stimulation. RA RegMos express less IL-10, which is positively correlated with serum VIP levels.…”

“…By expressing IL-10, RegMos can inhibit T eff proliferation. Such activities were found in monocytes upon exposure to microbial products [21]; B regs can also suppress other immune cell activities upon correct stimulation. Our previous work showed that B regs released TGF-β in response to re-exposure to endothelial cellderived exosomes, which suppressed T eff proliferation [22].…”