Helminth-induced Ly6Chi monocyte-derived alternatively activated macrophages suppress experimental autoimmune encephalomyelitis

Abstract

Helminths cause chronic infections and affect the immune response to unrelated inflammatory diseases. Although helminths have been used therapeutically to ameliorate inflammatory conditions, their anti-inflammatory properties are poorly understood. Alternatively activated macrophages (AAMϕs) have been suggested as the anti-inflammatory effector cells during helminth infections. Here, we define the origin of AAMϕs during infection with Taenia crassiceps, and their disease-modulating activity on the Experimental Autoimmune Encephalomyelitis (EAE). Our data show two distinct populations of AAMϕs, based on the expression of PD-L1 and PD-L2 molecules, resulting upon T. crassiceps infection. Adoptive transfer of Ly6C+ monocytes gave rise to PD-L1+/PD-L2+, but not PD-L1+/PD-L2− cells in T. crassiceps-infected mice, demonstrating that the PD-L1+/PD-L2+ subpopulation of AAMϕs originates from blood monocytes. Furthermore, adoptive transfer of PD-L1+/PD-L2+ AAMϕs into EAE induced mice reduced disease incidence, delayed disease onset, and diminished the clinical disability, indicating the critical role of these cells in the regulation of autoimmune disorders.

Granulomatous responses in larval taeniid infections

“…In chronic T. crassiceps infection, a pivotal element of immune suppression are macrophages expressing the two PD‐1 ligands, PD‐L1 and PD‐L2 . Although as mentioned both resident and recruited macrophages acquire other M (IL‐4) markers, only macrophages derived from inflammatory monocytes become PD‐L1/ PD‐L2 + …”

“…Macrophage polarization and recruitment have been studied in peritoneal T. crassiceps infection . In this system, there is little monocyte recruitment during early infection (up to 2 weeks), but in later stages, recruited cells replace resident ones .…”

“…Proliferation has not been directly studied, and its contribution cannot be ruled out in the early stages and in fact also not in the late stages, as recruited macrophages can proliferate . In T. crassiceps infection, both resident and recruited macrophages acquire M(IL‐4) phenotypes . Also in this system, the recruited monocytic cells express, in a IL‐4 receptor‐dependent fashion, the epithelial marker E‐cadherin, implicated in the formation of pseudo‐epithelial macrophage structures in granulomas …”

“…123 Macrophage polarization and recruitment have been studied in peritoneal T. crassiceps infection. [50][51][52][53]124,125 In this system, there is little monocyte recruitment during early infection (up to 2 weeks), but in later stages, recruited cells replace resident ones. 125 Proliferation has not been directly studied, and its contribution cannot be ruled out in the early stages and in fact also not in the late stages, as recruited macrophages can proliferate.…”

“…phenotypes. 125 Also in this system, the recruited monocytic cells express, in a IL-4 receptor-dependent fashion, the epithelial marker E-cadherin, implicated in the formation of pseudo-epithelial macrophage structures in granulomas. 6,124,126 Of potential relevance to eosinophil recruitment, the chemokines eotaxin-1 (CCL11) and RANTES (CCL5) are expressed in tissue around (degenerating, but not viable) cysticerci in pig brain.…”