CD18 Regulates Monocyte Hematopoiesis and Promotes Resistance to Experimental Schistosomiasis

Abstract

Infection with Schistosoma mansoni causes a chronic parasitic disease that progress to severe liver and gastrointestinal damage, and eventually death. During its development into mammalian hosts, immature schistosomula transit through the lung vasculature before they reach the liver to mature into adult worms. A low grade inflammatory reaction is induced during this process. However, molecules that are required for efficient leukocyte accumulation in the lungs of S. mansoni-infected subjects are unknown. In addition, specific leukocyte subsets that mediate pulmonary response during S. mansoni migration through the lung remain to be elucidated. β2 integrins are fundamental regulators of leukocyte trans-endothelial migration and function. Therefore, we investigated their role during experimental schistosomiasis. Mice that express low levels of CD18 (the common β2 integrin subunit) and wild type C57BL/6 mice were subcutaneously infected with S. mansoni cercariae. Cellular profiles of lungs and livers were evaluated in different time points after infection by flow cytometry. Low levels of CD18 affected the accumulation of patrolling Ly6Clow, intermediate Ly6Cinter monocytes, monocyte-derived macrophages and monocyte-derived dendritic cells in the lungs 7 days after infection. This correlated with increased TNF-α levels. Strikingly, low CD18 expression resulted in monocytopenia both in the peripheral blood and bone marrow during acute infection. After 48 days, S. mansoni worm burdens were higher in the hepatic portal system of CD18low mice, which also displayed reduced hepatic accumulation of patrolling Ly6Clow and intermediate Ly6Cinter, but not inflammatory Ly6Chigh monocytes. Higher parasite burden resulted in increased granulomatous lesions in the liver, increased egg deposition and enhanced mortality. Overall, our data point for a fundamental role of CD18 for monocyte hematopoiesis during infection, which promotes an efficient host response against experimental schistosomiasis.

Monocyte and Macrophage-Mediated Pathology and Protective Immunity During Schistosomiasis

“…Based on the differential expression of surface markers, monocytes are classified as: inflammatory monocytes (classical) (mouse: Ly6C high CCR2 + CX 3 CR1 low ; human: CD14 high CD16 − ), which are robustly recruited to sites of inflammation (Geissmann et al, 2003), but return to the bone marrow after 3 days under steady state (Varol et al, 2007); and patrolling monocytes (non-classical) (mouse: Ly6C low CCR2 low CX 3 CR1 high; human: CD14 low/− CD16 high ), which patrol blood vessels and remain in the circulation for as long as 7 days (Auffray et al, 2007; Figure 2). Recently, we showed that low expression of CD18 (common subunit of β2 integrins) was associated with a reduction of monocyte subsets in bone marrow and blood of mice infected with S. mansoni (Souza et al, 2018). This correlated with increased parasite burden, egg deposition and mortality of mice.…”

“…Monocytes promote resistance to schistosomiasis (Nascimento et al, 2014;Souza et al, 2018;de Souza et al, 2019). Indeed, inflammatory monocyte depletion causes a severe weight loss and disrupts a protective Th2 response during S. mansoni infection (Nascimento et al, 2014).…”

Crotoxin-Induced Mice Lung Impairment: Role of Nicotinic Acetylcholine Receptors and COX-Derived Prostanoids

“…Infiltrating leukocytes were isolated from mice lung using the protocol reported by Souza and colleagues [14]. Briefly, the upper right lung lobule was collected, minced with sterile scissors in RPMI 1640 medium, and treated with digestion buffer containing 0.05 mg/mL liberase (Roche-Basel, Switzerland) and 0.5 mg/mL DNase (Sigma-Aldrich) for 45 min, at 37 • C, under shaking at 2000 rpm.…”

IL-22 Promotes IFN-γ-Mediated Immunity against Histoplasma capsulatum Infection

“…The same cellular suspension used for fungal burden determination in lungs was used for the immunophenotyping of lung parenchyma cells by flow cytometry, as previous described [45,46]. The cell suspension was filtered in a sterile filcon syringe type (BD Bioscience-San Jose, CA, USA), submitted to red blood cells lysis with ammonium-chloride-potassium (ACK) solution and the number of total cells isolated from lung parenchyma was determined in a Neubauer chamber.…”