Abstract
Circulating monocytes in the bloodstream typically migrate to other tissues and differentiate into tissue resident macrophages, the process being determined by the constituents of the microenvironments encountered. These may include microbes and their products. In this study, we investigated whether Moraxella catarrhalis Ubiquitous Surface Protein A1 (UspA1), known to bind to a widely expressed human cell surface receptor CEACAM1, influences monocyte differentiation as receptor engagement has been shown to have profound effects on monocytes. We used the recombinant molecules corresponding to the regions of UspA1 which either bind (rD-7; UspA1527–665) or do not bind (r6–8; UspA1659–863) to CEACAM1 and investigated their effects on CD206, CD80 and CD86 expression on freshly isolated human CD14+ monocytes from peripheral blood mononuclear cells (PBMC). Exposure to rD-7, but not r6–8, biased monocyte differentiation towards a CD14+CD206+ phenotype, with reduced CD80 expression. Monocytes treated with rD-7 also secreted high levels of IL-1ra and chemokine IL-8 but not IL-10 or IL-12p70. The effects of rD-7 were independent of any residual endotoxin. Unexpectedly, these effects of rD-7 were also independent of its ability to bind to CEACAM1, as monocyte pre-treatment with the anti-CEACAM antibody A0115 known to inhibit rD-7 binding to the receptor, did not affect rD-7-driven differentiation. Further, another control protein rD-7/D (a mutant form of rD-7, known not to bind to CEACAMs), also behaved as the parent molecule. Our data suggest that specific regions of M. catarrhalis adhesin UspA1 may modulate inflammation during infection through a yet unknown receptor on monocytes.
Highlights
Monocytes and macrophages are both indispensable effector cells critical in regulation of inflammation and in non-specific innate immune responses, the first line of defence against invading bacteria [1]
In order to investigate the effect of M. catarrhalis CEACAMbinding surface adhesin Ubiquitous Surface Protein A1 (UspA1) on monocyte differentiation and function, monocytes were incubated with the CEACAM-binding recombinant molecule rD-7 or a control molecule, r6–8, corresponding to a region of UspA1 not involved in CEACAM binding
In 1992, Stahl reported that the mannose receptor CD206 was not found on circulating monocytes, while it was abundantly expressed on differentiated macrophages [43] and the LPS-induced differentiation of monocytes to macrophages involved NFkB [42]
Summary
Monocytes and macrophages are both indispensable effector cells critical in regulation of inflammation and in non-specific innate immune responses, the first line of defence against invading bacteria [1]. They regulate adaptive immunity in a cell-cell contact dependent manner or with secreted pro-inflammatory or anti-inflammatory cytokines and chemokines [2]. Monocytes are the circulating precursors of tissue macrophages and dendritic cells [3,4], and macrophage colony-stimulating factor (M-CSF) is a potent monocyte/macrophage differentiation factor [5] During such differentiation, signals initiated by different cytokines and specific surface receptors modify the process generating either classically activated M1 macrophages or alternatively activated M2 macrophages, which exhibit significant differences in receptor, cytokine and chemokine expression, and effector function. Monocyte differentiation can be regulated by immunoglobulin superfamily receptors [13] including members of the carcinoembryonic antigen (CEA) family
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