CD18 coordinates monocyte development and differentiation into alternatively activated macrophages conferring resistance to Schistosoma mansoni infection

Author(s)

Camila de Oliveira Silva e Souza

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2021-08-18

Examining board members

Lucia Helena Faccioli; Paulo Marcos da Matta Guedes; Anderson de Sá Nunes

• Advisor: Lucia Helena Faccioli

Abstract

Schistosomiasis is a neglected helminth disease caused by worms of the genus Schistosoma spp. The disease affects poor and rural communities localized in tropical and sub-tropical regions and causes ~240,000 fatal outcomes every year. During its development into mammalian hosts, immature schistosomula transit through the vasculature before they reach the liver, where they mature into adult worms and later migrate to mesenteric venues, mate, and begin egg deposition. The immune response during this process leads to the recruitment of leukocytes that act by destroying a significant number of cercariae in the lung and trigger a type 2 granuloma formation around the eggs in the liver, a hallmark of chronic disease. The trafficking of leukocytes to affected tissues depends on chemokines and molecules involved in cellular adhesion. The functional β2 integrin subunit (CD18) is a fundamental regulator of leukocyte trans-endothelial migration. However, the role played by CD18 during experimental schistosomiasis remains unclear. We sought to address this knowledge gap using a mouse model that expresses low levels of CD18 (CD18low), thus resembling humans with moderate ITGB2 deficiency. We infected wild-type C57BL/6 mice (WT) and CD18low with cercariae of S. mansoni subcutaneously. Low CD18 expression leads to a decrease in the survival rate of these animals by increasing the parasite burden, eggs deposition in the feces and inflammatory infiltrated in the liver. The susceptibility observed in CD18low mice was correlated to failures in monocytopoiesis in the bone marrow. Mechanistically, CD18 affects the IRF8- dependent CD115 expression on the proliferating monocyte progenitor (pMo), leading to the accumulation of these cells and consequent reduction of the mature monocyte subsets in the bone marrow and peripheral blood. In the lung, low levels of CD18 affected the accumulation of patrolling Ly6Clow, intermediate Ly6Cinter monocytes, monocyte-derived macrophages (MDMs) and dendritic cells (MDCs) after one week of infection. In the chronic phase of disease, low levels of CD18 decreased the inflammatory Ly6Chigh CX3CR1low/- CD11b+ monocytes in the liver, and the adoptive transference of these cell to CD18low mice ameliorates the inflammatory infiltrate and fibrosis. Inflammatory Ly6Chigh monocytes differentiate and polarize in alternatively activated macrophages (AAMs), which promote tissue repair. Following this hypothesis, we confirmed that low levels of CD18 affected the expression of Il4, Chi3l3l and Arg1, which decrease AAMs in the liver. This correlated with decreased IL-10 levels. In conclusion, our data point for a fundamental role of CD18 in monocytes development and differentiation into AAMs, which promotes an efficient host response during experimental schistosomiasis. (AU)

• FAPESP's process: 18/22667-0 - The role of CD18 for generation and plasticity of monocyte during Schistosoma mansoni infection
• Grantee: Camila de Oliveira Silva e Souza
• Support Opportunities: Scholarships in Brazil - Doctorate