Abstract
Cellular stress responses are often engaged at sites of inflammation and can alter macrophage cytokine production. We now report that macrophages in distinct states of differentiation or in different temporal stages of inflammatory response exhibit differential sensitivity to cell stress mediated alterations in M1-like polarized inflammatory cytokine production. Tunicamycin (Tm) treatment of bone marrow derived macrophages (BMDM) cultured with M-CSF cultured bone marrow derived macrophages (M-BMDM) had markedly amplified M1-like responses to LPS, exhibiting higher levels of IL12p40 and IL12p35 mRNAs while BMDM cultured with GM-CSF, which normally express high IL12 subunit production in response to LPS, were relatively unaltered. Anti-inflammatory IL10 mRNA production in LPS-stimulated M-BMDM was greatly reduced by cell stress. These changes in cytokine mRNA levels resulted from altered rates of transcription and mRNA decay. Stress also altered cytokine protein production. Resident liver macrophages isolated from mice treated with Tm showed elevated levels of IL12 subunit mRNA production following LPS stimulation. Furthermore, macrophages infiltrating the liver during the early phase of acetaminophen injury (24 h) had little stress-mediated change in cytokine mRNA production while cells isolated in the later phase (48–72 h) exhibited higher sensitivity for stress elevated cytokine production. Hence cultured macrophages developed using different growth/differentiation factors and macrophages from different temporal stages of injury in vivo show markedly different sensitivity to cell stress for altered inflammatory cytokine production. These findings suggest that cellular stress can be an important modulator of the magnitude and character of myeloid inflammatory activity.
Highlights
It is well-recognized that phenotypic heterogeneity or plasticity within myeloid cells is an important feature in the pathogenesis of many acute and chronic disorders [1,2,3]
It is noteworthy that cellular stress pathways contribute to disease pathogenesis within multiple cell populations and the modulation of macrophage function by cell stress response has been reported by multiple laboratories [22,23,24,25,26,27,28]
The results demonstrate that the lower capacity of macrophage colony-stimulating factor (M-CSF)-cultured bone marrow derived macrophages (BMDM) for IL12 subunit production can be markedly enhanced by cellular stress while the elevated expression of IL12 in GM-CSF BMDM is not effected
Summary
It is well-recognized that phenotypic heterogeneity or plasticity within myeloid cells is an important feature in the pathogenesis of many acute and chronic disorders [1,2,3]. Macrophage lineage cell populations exhibit a broad array of activities in response to prototypic stimuli encountered in their local tissue microenvironment. It is worth noting that most macrophages in vivo do not exhibit hyper-polarized M1 or M2 phenotype and may exhibit M1 and M2 characteristics simultaneously. During response to injury or infection, the state of macrophage polarization has been shown to transition from M1 to M2 based upon the nature of the inflammatory environment and reflecting the change from inflammatory anti-microbial activity to the need for tissue restorative function [1, 7, 8]. The magnitude of M1 or M2 like responses can vary dramatically
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