THE ENDOGENOUS REGULATION OF THE HUMAN MACROPHAGE ACTIVATION RESPONSE

Abstract

Macrophages are innate immune cells that participate in host defense to invading

pathogens. They are powerful producers of cytokines and inflammatory mediators due to

their efficient recognition of pathogen associated molecular patterns (PAMPs) via toll

like receptors (TLRs). We and others have shown that the activation response to PAMPs

is transient. In the present work, we demonstrate that stimulated macrophages produce

adenosine and prostaglandin E2, which function as regulators of the macrophage

activation response. Macrophages also upregulate receptors for these regulators to

terminate inflammation and promote wound healing. We performed high throughput

RNA sequencing to characterize the transcriptomes of human monocyte-derived

macrophages in response to stimulation with LPS + Adenosine or LPS + PGE2. These

cells exhibited a decrease in inflammatory transcripts and an increase in transcripts

associated with cell growth and repair when compared to cells stimulated in the absence

of these regulators.

Macrophages can be generated from precursor cells in response to two different

growth factors; M-CSF (macrophage colony stimulating factor) and GM-CSF

(granulocyte-macrophage colony stimulating factor). M-CSF is expressed constitutively

in a variety of tissues, while GM-CSF is expressed primarily in the lung, but can be

induced in other tissues under inflammatory conditions. We demonstrate that human

macrophages differentiated in M-CSF readily adopt an anti-inflammatory, growth

promoting phenotype in response to LPS + Adenosine or LPS + PGE2, while

macrophages differentiated in GM-CSF do not. This observation suggests that M-CSF

derived human macrophages may be better able to alter their activation state in response

to surrounding signals in order to maintain homeostasis. GM-CSF derived macrophages,

in contrast, may undergo a more prominent activation response that is associated with

inflammation and tissue destruction due to their inability to efficiently respond to

resolving molecules.