Identification of a Unique Hybrid Macrophage-Polarization State following Recovery from Lipopolysaccharide Tolerance

Abstract

LPS tolerance is an essential immune-homeostatic response to repeated exposure to LPS that prevents excessive inflammatory responses. LPS tolerance induces a state of altered responsiveness in macrophages, resulting in repression of proinflammatory gene expression and increased expression of factors that mediate the resolution of inflammation. In this study, we analyzed the transcriptional plasticity of macrophages following LPS tolerance using genome-wide transcriptional profiling. We demonstrate that LPS tolerance is a transient state and that the expression of proinflammatory genes is restored to levels comparable to the acute response to LPS. However, following recovery from LPS tolerance a number of genes remained locked in a tolerizable state, including IL-33, CD86, IL-10, and NFIL3. Furthermore, we identified of a number of genes uniquely induced following recovery from LPS tolerance. Thus, macrophages adopt a unique transcriptional profile following recovery from LPS tolerance and have a distinct expression pattern of regulators of Ag presentation, antiviral responses, and transcription factors. Our data suggest that recovery from LPS tolerance leads to a hybrid macrophage activation state that is proinflammatory and microbicidal in nature but that possesses a regulatory anti-inflammatory profile distinct from that of LPS-tolerant and LPS-activated macrophages.

Comparative transcriptome analysis of equine alveolar macrophages

“…By contrast, the highly expressed transcripts identified in PMs may reflect either a classical [M1] (CXCL1, CXCL3, IL1A, IL1B, IL8, NFKB2) or an alternative [M2] (CCL22, IL4R, IL10) phenotype. Although a more activated state in PMs might be supported by the greater expression of the acute phase protein PTX3 and several interferons (IFNA1, IFNA2), certain PM transcripts (IFNA2, IL6) are more supportive of a novel state of hybrid polarisation recently reported in murine LPS-tolerant macrophages [25]. Both of these features may partly explain the previously reported nonresponsiveness of horse PMs to an LPS stimulus [4].…”

Probing the molecular regulation of lipopolysaccharide stress in piglet liver by comparative proteomics analysis

“…The transcription factors regulate various cellular genes involving cytokines and chemokines, which promote the recruitment and activation of leukocytes that are essential for eradicating the foreign cells . However, excessive inflammatory reactions lead to intestinal tissue damage . Our laboratory has a long‐standing research interest in understanding molecular mechanisms of LPS‐induced immunological stress using weaned piglets as a model.…”

The Ground State of Innate Immune Responsiveness Is Determined at the Interface of Genetic, Epigenetic, and Environmental Influences

“…This forms a repressive complex that can be reset to allow reactivation of the inflammatory program after a period of recovery. Tolerance is not as transient as once thought: global transcriptome and histone profiling of LPS tolerance in mouse bone marrowderived macrophages demonstrated some longer-term effects (25,26). Even after 4 d of recovery, LPS tolerance led to longterm loss of IL-10 and costimulatory molecules CD80 and CD86, as well as upregulation of a number of chemokine receptors.…”

“…It is not yet clear whether additional chromatin modifications are associated with these longer-term changes in the tolerance-recovered macrophage. The levels of the p50 subunit remain high (24), but genes that do not reset to pre-LPS levels appear to be regulated in a p50-independent manner (25), and histone marks classically associated with actively transcribed genes can be found at the tolerance-resistant loci (26).…”