Absence of Tumor Necrosis Factor Supports Alternative Activation of Macrophages in the Liver after Infection with Leishmania major

Abstract

The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major in normally resistant C57BL/6J (B6.WT) mice. The underlying pathogenic mechanism of this fatal disease has so far remained elusive. We found that B6.WT mice deficient for the tnf gene (B6.TNF−/−) displayed not only a non-healing cutaneous lesion but also a serious infection of the liver upon L. major inoculation. Infected B6.TNF−/− mice developed an enlarged liver that showed increased inflammation. Furthermore, we detected an accumulating monocyte-derived macrophage population (CD45+F4/80+CD11bhiLy6Clow) that displayed a M2 macrophage phenotype with high expression of CD206, arginase-1, and IL-6, supporting the notion that IL-6 could be involved in M2 differentiation. In in vitro experiments, we demonstrated that IL-6 upregulated M-CSF receptor expression and skewed monocyte differentiation from dendritic cells to macrophages. This was countered by the addition of TNF. Furthermore, TNF interfered with the activation of IL-6-induced gp130-signal transducer and activator of transcription (STAT) 3 and IL-4-STAT6 signaling, thereby abrogating IL-6-facilitated M2 macrophage polarization. Therefore, our results support the notion of a general role of TNF in the inflammatory activation of macrophages and define a new role of IL-6 signaling in macrophage polarization downstream of TNF.

Deep phosphoproteome analysis of Schistosoma mansoni leads development of a kinomic array that highlights sex-biased differences in adult worm protein phosphorylation

“…Research, particularly during the past decade, provides insights into some of these differentially phosphorylated proteins/putative upstream protein kinases in adult schistosomes. For example: 1) AMPK expression is down-regulated in S. mansoni isolated from immunodeficient mice suggesting that modulation of the worms' energy metabolism may contribute to reduced growth and reproductive fitness in such hosts [95]. 2) Akt, a putative upstream kinase for CDK/PITSLRE and VAL 6 (a possible vaccine target) is highly active in the adult schistosome tegument and plays an important regulatory role in glucose uptake via SGTP4 [15]; inhibition of Akt also attenuates pairing and egg laying of adult S. mansoni [96].…”

Adding MASP1 to the lectin pathway—Leprosy association puzzle: Hints from gene polymorphisms and protein levels

“…However, investigating the immune response elicited by M. leprae PLOS NEGLECTED TROPICAL DISEASES remains a particular challenge, due to its extreme dependence on the human host. Genetic disease association studies shed light on a wide range of aspects from the onset of infection to disease classification, by uncovering genes whose protein products may play pivotal roles in this pathology [40]. This has been the case for several genes of the lectin pathway of complement; those encoding PRMs, MBL2 [6,11] [7], FCN1 [5], FCN2 [9] and FCN3 [14], the serine protease MASP2 [8] and the MBL receptor encoded by CR1 [15].…”

Human Dendritic Cells Express the Complement Receptor Immunoglobulin Which Regulates T Cell Responses

“…The cytokines TNF-α, IL-1β, and IL-6 are pyrogenic cytokines (20,21) which have direct effects on monocytic cells, including the modulation of macrophage and DC differentiation (22)(23)(24)(25) or macrophage function and cell death (26,27). Since these are produced during the innate phase of the inflammatory response, they may influence the adaptive immune response through their effects on DC.…”