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Cited by 224Immune Response and InflammationImmune responses and vaccinationsImmune cells in cancer

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Innate Immune Programing by Endotoxin and Its Pathological Consequences

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Morris, Matthew C., Gilliam, Elizabeth A., Li, Liwu·2015·Frontiers in Immunology
DOI 10.3389/fimmu.2014.00680PMC PMC4285116
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Abstract

Monocytes and macrophages play pivotal roles in inflammation and homeostasis. Recent studies suggest that dynamic programing of macrophages and monocytes may give rise to distinct "memory" states. Lipopolysaccharide (LPS), a classical pattern recognition molecule, dynamically programs innate immune responses. Emerging studies have revealed complex dynamics of cellular responses to LPS, with high doses causing acute, resolving inflammation, while lower doses are associated with low-grade and chronic non-resolving inflammation. These phenomena hint at dynamic complexities of intra-cellular signaling circuits downstream of the Toll-like receptor 4 (TLR4). In this review, we examine pathological effects of varying LPS doses with respect to the dynamics of innate immune responses and key molecular regulatory circuits responsible for these effects.

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Crossref · 10.3389/fimmu.2014.00680

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Figures

Figure 1 Overview of signaling cascades engaged by TLR4. LPS triggers recruitment of various adaptor molecules that may recruit a myriad of downstream kinases and transcription factors, resulting in the activation of both pro- and anti-inflammatory responses. However, the dynamic modulation and coordination of these complex events are not well understood.
Figure 1 Overview of signaling cascades engaged by TLR4. LPS triggers recruitment of various adaptor molecules that may recruit a myriad of downstream kinases and transcription factors, resulting in the activation of both pro- and anti-inflammatory responses. However, the dynamic modulation and coordination of these complex events are not well understood.CC BY · PubMed Central
Figure 2 Competitive molecular circuits potentially responsible for the dynamic programing of innate leukocytes. Varying doses of LPS may engage unique TLR4 complexes that may cause intra-cellular pathway switching, leading to either low-grade non-resolving inflammation, or acute resolving inflammation. Super-low-dose LPS selectively activates GSK3 and JNK, while suppressing AKT and ERK. These two branches may also have mutually inhibitory interactions, further fine-tuning cellular inflammatory states. Low- to high-dose LPS potently induces NFκB and MAP kinases, leading to robust inflammatory reactions. On the other hand, low- to high-dose LPS could also trigger the activation of AKT and ERK, which may serve to dampen inflammatory responses. IRAK-1 appears to be critical for both the low-grade inflammation triggered by super-low-dose LPS and the anti-inflammatory responses (e.g., IL-10 expression through ERK activation) activated by high-dose LPS.
Figure 2 Competitive molecular circuits potentially responsible for the dynamic programing of innate leukocytes. Varying doses of LPS may engage unique TLR4 complexes that may cause intra-cellular pathway switching, leading to either low-grade non-resolving inflammation, or acute resolving inflammation. Super-low-dose LPS selectively activates GSK3 and JNK, while suppressing AKT and ERK. These two branches may also have mutually inhibitory interactions, further fine-tuning cellular inflammatory states. Low- to high-dose LPS potently induces NFκB and MAP kinases, leading to robust inflammatory reactions. On the other hand, low- to high-dose LPS could also trigger the activation of AKT and ERK, which may serve to dampen inflammatory responses. IRAK-1 appears to be critical for both the low-grade inflammation triggered by super-low-dose LPS and the anti-inflammatory responses (e.g., IL-10 expression through ERK activation) activated by high-dose LPS.CC BY · PubMed Central
Figure 3 The course of acute and persistent inflammatory responses. The upper panel depicts the trajectory of a typical inflammatory response. An initial pro-inflammatory phase characterized by recruitment of neutrophils and production of cytokines such as IL-6 and TNFα is followed by resolution, with compensatory induction of anti-inflammatory cytokines (e.g., IL-10, TGFβ). Non-resolving and persistent inflammation is mild but unopposed by anti-inflammatory mechanisms.
Figure 3 The course of acute and persistent inflammatory responses. The upper panel depicts the trajectory of a typical inflammatory response. An initial pro-inflammatory phase characterized by recruitment of neutrophils and production of cytokines such as IL-6 and TNFα is followed by resolution, with compensatory induction of anti-inflammatory cytokines (e.g., IL-10, TGFβ). Non-resolving and persistent inflammation is mild but unopposed by anti-inflammatory mechanisms.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Wu, 2000, Projection of Chronic Illness Prevalence and Cost Inflation
  2. Ogden, 2007, Obesity Among Adults in the United States – No Change Since 2003–2004. NCHS Data Brief
  3. Anderson, 2004, Chronic Conditions: Making the Case for Ongoing Care. Partnership for Solutions

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Metadata

Authors
Morris, M. C., Gilliam, E. A., & Li, L.
Affiliations
Virginia Tech (US)
Corresponding author
Li, Liwu
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2015-01-06
Volume
5
Pages
680-680
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2014.00680
PMC
PMC4285116
OpenAlex
W1994176403
Cited by
224
References
117
Citations by year
2026: 7 · 2025: 12 · 2024: 11 · 2023: 19 · 2022: 16 · 2021: 16 · 2020: 14 · 2019: 21 · 2018: 24 · 2017: 28 · 2016: 26 · 2015: 28
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • VTechWorks (Virginia Tech) (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL115835)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
lipopolysaccharide, endotoxin, innate immunity, monocytes, macrophages, macrophage polarization, TLR4, low-grade inflammation, acute inflammation

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